Tricyclic compounds useful to treat orthomyxovirus infections

ABSTRACT

The present invention provides a compound of Formula (I) including pharmaceutically acceptable salts thereof: 
                         
and therapeutic uses of these compounds. The invention further provides pharmaceutical compositions comprising these compounds, compositions comprising these compounds with a therapeutic co-agent, and methods of using the compounds and compositions to treat viral infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/IB2017/051338, filed Mar. 7, 2017, which claims the benefit ofpriority to U.S. Provisional Application No. 62/305,392, filed Mar. 8,2016, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention provides compounds that inhibit orthomyxovirusreplication, and are accordingly useful for treatment of viralinfections caused by orthomyxoviruses. The invention further providespharmaceutical compositions containing these compounds and methods ofusing these compounds to treat or prevent viral infections caused byorthomyxovirus.

BACKGROUND

Orthomyxoviruses have negative-sense single stranded RNA genomes, andreplicate in the nucleus of infected cells, as they lack the machineryto generate the cap structure to produce their own mRNA. Members of theOrthomyxovirus Family have an RNA-dependent RNA polymerase withendonuclease activity that cleaves a section of the capped 5′-end ofcellular mRNA; the RNA polymerase then uses the cleavage product as aprimer for synthesis of viral mRNA. This process is known ascap-snatching. This endonuclease has been recognized as a promisingtarget for development of antivirals effective against orthomyxoviruses.ACS Med. Chem. Letters, 2014, vol. 5, 61-64. Inhibitors of thisendonuclease have been disclosed, for example, in WO2015/038660 andUS2015/0072982, WO2010/147068, and US2013/0197219, which report thatsuch inhibitors are useful to treat influenza infections in mammals.

The orthomyxovirus family includes influenza A, influenza B andinfluenza C, all of which can infect humans, as well as several othergenera of viruses that generally do not infect humans. Influenza A isthe most virulent of these pathogens in humans, often accounting for themajority of serious cases of influenza during a typical flu season. Itis estimated that influenza kills as many as 40,000 people per year inthe U.S., in spite of the widespread use of vaccines to reduce theincidence of influenza; thus there is a great need for antiviraltherapeutics effective to treat influenza, especially influenza A. Thepresent invention provides compounds that inhibit replication oforthomyxoviruses, including influenza A, influenza B and influenza C.Without being bound by theory, it is believed these compounds achievetheir antiviral effects by inhibiting the endonuclease function of theviral polymerase. Because this endonuclease is highly conserved acrossinfluenza A viruses (id.), the compounds are especially useful fortreatment of influenza A.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

G is H or a group selected from —C(O)R, —C(O)—OR, —C(R^(G))₂—O—C(O)R,—C(R^(G))₂—O—C(O)—OR, —C(O)—NR₂, and —C(R^(G))₂—O—C(O)NR₂, where each Ris independently C₁-C₄ alkyl, phenyl, pyridyl, C₃-C₇ cycloalkyl, or a3-6 membered heterocyclic ring containing one or two heteroatomsselected from N, O and S as ring members; and each R is optionallysubstituted with one or two groups selected from halo, CN, —OH, amino,C₁₋₄ alkyl, phenyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

-   -   and each R^(G) is independently selected from H and C₁₋₄ alkyl;

X¹ is CR^(X1) or N, where R^(X1) is H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl,CN, COOH, or a 5-6 membered heteroaryl ring containing 1-4 heteroatomsselected from N, O and S as ring members and optionally substituted by1-2 groups selected from halo, hydroxy, amino, C₁₋₃ alkyl, C₁₋₃haloalkyl, and C₁₋₃ alkoxy;

X² is CR^(X2) or N, where R^(X2) is H, halo, C₁₋₆ alkyl or C₁₋₄haloalkyl;

X³ is CR^(X3) or N, where R^(X3) is H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

-   -   provided that X² is CR^(X2) if either or both of X¹ and X³        represent N;

R¹ is H, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkoxy;

R² and R³ are independently H, C₁₋₄ alkyl or C₃₋₅ cycloalkyl, whereineach C₁₋₄ alkyl and C₃₋₅ cycloalkyl is optionally substituted with oneor two groups selected from halo, CN, —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy;

-   -   or R² and R³ taken together with the carbon atom to which both        are attached can form a 3-5 membered cycloalkyl ring or a 3-5        membered cyclic ether ring having one oxygen as a ring member;

Ring A is a five-membered heteroaryl ring containing at least one carbonring atom and up to four heteroatoms selected from N, O and S as ringmembers, wherein

-   -   Z¹ is N, O or S;    -   Z² and Z³ are independently CR^(z), N, NR^(z), O or S; and    -   Z⁴ and Z⁵ each independently represent C or N,        -   provided Z⁴ and Z⁵ are not both simultaneously N,        -   where each R^(z) is independently selected from H, halo,            C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl            containing one or two heteroatoms selected from N, O and S            as ring members, C₁₋₄ alkoxy, CN, CON(R⁴)₂ and C₁₋₄            haloalkyl, wherein the C₁₋₄ alkyl is optionally substituted            with one or two groups selected from —OR⁴, —N(R⁴)₂, COOR⁴,            CON(R⁴)₂, and a 5-6 membered heterocyclic ring containing            one or two heteroatoms selected from N, O and S as ring            members;

R⁴ at each occurrence is independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, phenyl, a 5-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, and 5-6membered heterocyclic ring containing one or two heteroatoms selectedfrom N, O and S as ring members are each optionally substituted with oneor two groups independently selected from halo, —OH, C₁₋₂ alkyl, and—O(C₁₋₂ alkyl);

-   -   and two R⁴ groups directly attached to the same nitrogen atom        can optionally be taken together to form a 4-6 membered        heterocycle optionally containing an additional heteroatom        selected from N, O and S as a ring member and optionally        substituted with one or two groups selected from halo, —OH, C₁₋₂        alkyl, and —O(C₁₋₂ alkyl);

Ar¹ and Ar² each represent phenyl or a 5-6 membered heteroaryl ringcontaining 1-3 heteroatoms selected from N, O and S as ring members, andare each independently substituted with up to three groups selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, —S(C₁₋₃ alkyl), —SO₂(C₁₋₃ alkyl), and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic ring system        wherein each Ar¹ and Ar² is optionally substituted by up to two        groups independently selected from halo, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, —S(C₁₋₃        alkyl), —SO₂(C₁₋₃ alkyl), and CN,    -   where L is selected from S, S═O, SO₂, O, C(R^(L))₂ and CF₂,    -   and each R^(L) is independently H or C₁₋₂ alkyl;        which are further described herein.

The compounds of Formula (I) are inhibitors of the endonuclease functionof influenza viruses as shown by the data provided herein, and theyinhibit replication of influenza viruses. Accordingly, these compoundsare useful to treat or prevent orthomyxovirus infections in mammalssusceptible to such infections, and are particularly useful to treatinfluenza virus infections in humans. They are also useful to inhibitreplication of orthomyxoviruses, including influenza viruses, in cells.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of Formula (I) admixed with at least onepharmaceutically acceptable carrier or excipient, optionally admixedwith two or more pharmaceutically acceptable carriers or excipients.

In another aspect, the invention provides a method to treat a subjectinfected with influenza A, B or C, which comprises administering to asubject in need of such treatment an effective amount of a compound ofFormula (I) or any subgenus or species thereof as described herein, or apharmaceutical composition comprising such compound. The subject can bea mammal, and is preferably a human, although the compounds and methodsof the invention are suitable for treatment of other species thatcontract Influenza A, Influenza B, or influenza C, as well as otherorthomyxoviruses. The invention includes compounds of Formula (I) andthe subgenera of Formula (I) described herein, and all stereoisomers(including diastereoisomers and enantiomers) except where a specificisomer is expressly described, as well as tautomers and isotopicallyenriched versions thereof (including deuterium substitutions) as well aspharmaceutically acceptable salts of these compounds. Compounds of thepresent invention also comprise polymorphs of compounds of formula I (orsubformulae thereof) and salts thereof.

DETAILED DESCRIPTION

The following definitions apply unless otherwise expressly provided:

As used herein, the term “halogen” or halo refers to fluorine, bromine,chlorine or iodine, in particular it refers to fluorine or chlorine whenattached to an alkyl group, and further includes bromine or iodine whenon an aryl or heteroaryl group.

As used herein, unless otherwise specified, the term “heteroatoms”refers to nitrogen (N), oxygen (O) or sulfur (S) atoms.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 10 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 6carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like. A substituted alkyl is an alkylgroup containing one or more substituents in place of hydrogen, such asone, two, or three substituents, up to the number of hydrogens presenton the unsubstituted alkyl group. Suitable substituents for alkylgroups, if not otherwise specified, may be selected from halogen, CN,oxo, hydroxy, C₁₋₄ alkoxy, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted phenyl, amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄ alkylthio, C₁₋₄ alkylsulfonyl, —C(═O)—C₁₋₄alkyl, COOH, COO(C₁₋₄ alkyl), —O(C═O)— C₁₋₄ alkyl, —NHC(═O)C₁₋₄ alkyland —NHC(═O)OC₁₋₄ alkyl groups, where substituents for the substitutedcycloalkyl or phenyl are up to three groups selected from Me, Et, —OMe,—OEt, CF₃, halo, CN, OH, and NH₂.

As used herein, the term “alkylene” refers to a divalent alkyl grouphaving 1 to 10 carbon atoms, and two open valences to attach to otherfeatures. Unless otherwise provided, alkylene refers to moieties having1 to 6 carbon atoms. Representative examples of alkylene include, butare not limited to, methylene, ethylene, n-propylene, iso-propylene,n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene,isopentylene, neopentylene, n-hexylene, 2,2-dimethylbutylene, and thelike. A substituted alkylene is an alkylene group containing one ormore, such as one, two or three substituents; unless otherwisespecified, suitable substituents for an alkylene group are selected fromthe substituents listed above for alkyl groups.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, which is substituted by one or more halo groups. The haloalkylcan be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one chloro or fluorowithin the alkyl group. Chloro and fluoro are commonly present assubstituents on alkyl or cycloalkyl groups; fluoro, chloro and bromo areoften present on aryl or heteroaryl groups. Dihaloalkyl andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups on the alkyl. Typically thepolyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Aperhalo-alkyl refers to an alkyl having all hydrogen atoms replaced withhalo atoms, e.g, trifluoromethyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined above. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy,pentyloxy, hexyloxy, and the like. Typically, alkoxy groups have 1-6carbons, more commonly 1-4 carbon atoms.

A “substituted alkoxy” is an alkoxy group containing one or more, suchas one, two or three substituents on the alkyl portion of the alkoxy.Unless otherwise specified, suitable substituents are selected from thesubstituents listed above for alkyl groups, except that hydroxyl andamino are not normally present on the carbon that is directly attachedto the oxygen of the substituted ‘alkyl-0’ group.

Similarly, each alkyl part of other groups like “alkylaminocarbonyl”,“alkoxyalkyl”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”,“alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall havethe same meaning as described in the above-mentioned definition of“alkyl”. When used in this way, unless otherwise indicated, the alkylgroup is often a 1-4 carbon alkyl and is not further substituted bygroups other than the component named. When such alkyl groups aresubstituted, suitable substituents are those named above for alkylgroups unless, otherwise specified.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, whereinhaloalkyl is defined above. Representative examples of haloalkoxyinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, trichloromethoxy, 2-chloroethoxy,2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like.Typically, haloalkyl groups have 1-4 carbon atoms.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatednon-aromatic monocyclic, bicyclic, tricyclic or spirocyclic hydrocarbongroups of 3-12 carbon atoms: the cycloalkyl group may be unsaturated,and may be fused to another ring that can be saturated, unsaturated oraromatic, provided the ring atom of the cycloalkyl group that isconnected to the molecular formula of interest is not an aromatic ringcarbon. Unless otherwise provided, cycloalkyl refers to cyclichydrocarbon groups having between 3 and 9 ring carbon atoms or between 3and 7 ring carbon atoms. Preferably, cycloalkyl groups are saturatedmonocyclic rings having 3-7 ring atoms, such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, unless otherwise specified.

A substituted cycloalkyl is a cycloalkyl group substituted by one, ortwo, or three, or more than three substituents, up to the number ofhydrogens on the unsubstituted group. Typically, a substitutedcycloalkyl will have 1-4 substituents unless otherwise specified.Suitable substituents, unless otherwise specified, are independentlyselected from the group consisting of halogen, hydroxyl, thiol, cyano,nitro, oxo, C1-C4-alkylimino, C1-C4-alkoximino, hydroxyimino,C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy,C1-C4-thioalkyl, C2-C4-alkenyloxy, C2-C4-alkynyloxy,C1-C4-alkylcarbonyl, carboxy, C1-C4-alkoxycarbonyl, amino,C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkylaminocarbonyl,di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino,C1-C4-alkylcarbonyl(C1-C4-alkyl)amino, C1-C4-alkylsulfonyl,C1-C4-alkylsulfamoyl, and C1-C4-alkylaminosulfonyl, where each of theaforementioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl, alkoxyresidues) may be further substituted by one or more groups independentlyselected at each occurrence from the list of substituents for ‘alkyl’groups herein. Preferred substituents for a cycloalkyl group includeC1-C4 alkyl and the substituent groups listed above as suitablesubstituents for alkyl groups.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

Similarly, each cycloalkyl part of other groups like “cycloalkyloxy”,“cycloalkoxyalkyl”, “cycloalkoxycarbonyl”, “cycloalkoxy-carbonylalkyl”,“cycloalkylsulfonyl”, “halocycloalkyl” shall have the same meaning asdescribed in the above-mentioned definition of “cycloalkyl”. When usedin these terms, the cycloalkyl is typically a monocyclic 3-7 carbonring, that is unsubstituted or substituted with 1-2 groups. Whenoptionally substituted, the substituents are typically selected fromC1-C4 alkyl and those set forth above as suitable for alkyl groups.

As used herein, the term “aryl” refers to an aromatic hydrocarbon grouphaving 6-14 carbon atoms in the ring portion. Typically, aryl ismonocyclic, bicyclic or tricyclic aryl having 6-14 carbon atoms, often6-10 carbon atoms, e.g., phenyl or naphthyl. Furthermore, the term“aryl” as used herein, refers to an aromatic substituent which can be asingle aromatic ring, or multiple aromatic rings that are fusedtogether. Non-limiting examples include phenyl, naphthyl and1,2,3,4-tetrahydronaphthyl, provided the tetrahydronaphthyl is connectedto the formula being described through a carbon of the aromatic ring ofthe tetrahydronaphthyl group. Unless otherwise indicated, a preferredaryl group is phenyl.

A substituted aryl is an aryl group substituted by 1-5 (such as one, ortwo, or three) substituents independently selected from the groupconsisting of hydroxyl, thiol, cyano, nitro, C1-C4-alkyl, C2-C4-alkenyl,C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-thioalkyl, C2-C4-alkenyloxy,C2-C4-alkynyloxy, halogen, C1-C4-alkylcarbonyl, carboxy,C1-C4-alkoxycarbonyl, amino, C1-C4-alkylamino, di-C1-C4-alkylamino,C1-C4-alkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl,C1-C4-alkylcarbonylamino, C1-C4-alkylcarbonyl(C1-C4-alkyl)amino,C1-C4-alkylsulfonyl, sulfamoyl, C1-C4-alkylsulfamoyl, andC1-C4-alkylaminosulfonyl where each of the aforementioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more groups independently selected at eachoccurrence from the groups listed above as suitable substituents foralkyl groups. Preferred substituents for a substituted aryl group areC₁₋₄ alkyl and those groups named above as suitable substituents foralkyl groups, excluding divalent groups such as oxo.

Similarly, each aryl part of other groups like “aryloxy”,“aryloxyalkyl”, “aryloxycarbonyl”, “aryloxy-carbonylalkyl” shall havethe same meaning as described in the above-mentioned definition of“aryl”.

As used herein, the term “heterocyclyl” refers to a heterocyclic radicalthat is saturated or partially unsaturated but not aromatic, and can bea monocyclic or a polycyclic ring (in case of a polycyclic ringparticularly a bicyclic, tricyclic or spirocyclic ring); and has 3 to14, more commonly 4 to 10, and most preferably 5 or 6 ring atoms;wherein one or more, preferably one to four, especially one or two ringatoms are heteroatoms independently selected from O, S and N (theremaining ring atoms therefore being carbon). Even if it is describedas, e.g., a C5-6 atom ring, a heterocycle contains at least oneheteroatom as a ring atom with the other ring atoms being carbon, andhas the number of ring atoms stated, e.g. 5-6 in this example.Preferably, a heterocyclyl group has one or two such heteroatoms as ringatoms, and preferably the heteroatoms are not directly connected to eachother. The bonding ring (i.e. the ring connecting to the Formula ofinterest) preferably has 4 to 12, especially 5 to 7 ring atoms unlessotherwise specified. The heterocyclic group can be fused to an aromaticring, provided the atom of the heterocyclic group attached to theFormula of interest is not aromatic. The heterocyclic group can beattached to the Formula of interest via a heteroatom (typicallynitrogen) or a carbon atom of the heterocyclic group. The heterocyclylcan include fused or bridged rings as well as spirocyclic rings, andonly one ring of a polycyclic heterocyclic group needs to contain aheteroatom as a ring atom. Examples of heterocycles includetetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, and the like.

A substituted heterocyclyl is a heterocyclyl group independentlysubstituted by 1-5 (such as one, or two, or three) substituents selectedfrom the substituents described above for a cycloalkyl group.

Similarly, each heterocyclyl part of other groups like“heterocyclyloxy”, “heterocyclyloxyalkyl”, “heterocyclyloxycarbonyl”shall have the same meaning as described in the above-mentioneddefinition of “heterocyclyl”.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to8 heteroatoms as ring members, with the remaining ring atoms beingcarbon, and the heteroatoms are selected from N, O and S. Typically, theheteroaryl is a 5-10 membered ring system, especially a 5-6 memberedmonocyclic or an 8-10 membered bicyclic group. Typical heteroaryl groupsinclude 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-,4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl,3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, 1- or 2-tetrazolyl,2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings.Non-limiting examples include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-,or 7-benzothiazolyl.

A substituted heteroaryl is a heteroaryl group containing one or moresubstituents, typically one or two substituents, selected from thesubstituents described above as suitable for an aryl group.

Similarly, each heteroaryl part of other groups like “heteroaryloxy”,“heteroaryloxyalkyl”, “heteroaryloxycarbonyl” shall have the samemeaning as described in the above-mentioned definition of “heteroaryl”.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments of thepresent invention.

In a first embodiment (Embodiment 1), the invention provides a compoundof the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

G is H or a group selected from —C(O)R, —C(O)—OR, —C(R^(G))₂—O—C(O)R,—C(R^(G))₂—O—C(O)—OR, —C(O)—NR₂, and —C(R^(G))₂—O—C(O)NR₂, where each Ris H or a group independently selected from C₁-C₄ alkyl, phenyl,pyridyl, C₃-C₇ cycloalkyl, and a 3-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers; and each R that is not H is optionally substituted with one ortwo groups selected from halo, CN, —OH, amino, C₁₋₄ alkyl, phenyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

-   -   and each R^(G) is independently selected from H and C₁₋₄ alkyl;

X¹ is CR^(X1) or N, where R^(X1) is H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl,CN, COOH, or a 5-6 membered heteroaryl ring containing 1-4 heteroatomsselected from N, O and S as ring members and optionally substituted by1-2 groups selected from halo, hydroxy, amino, C₁₋₃ alkyl, C₁₋₃haloalkyl, and C₁₋₃ alkoxy;

X² is CR^(X2) or N, where R^(X2) is H, halo, C₁₋₆ alkyl or C₁₋₄haloalkyl;

X³ is CR^(X3) or N, where R^(X3) is H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

-   -   provided that X² is CR^(X2) if either or both of X¹ and X³        represent N;

R¹ is H, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkoxy;

R² and R³ are independently H, C₁₋₄ alkyl or C₃₋₆ cycloalkyl, whereineach C₁₋₄ alkyl and C₃₋₅ cycloalkyl is optionally substituted with oneor two groups selected from halo, CN, —OH, C₁₋₄ alkoxy, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy;

-   -   or R² and R³ taken together with the carbon atom to which both        are attached can form a 3-5 membered cycloalkyl ring or a 3-5        membered cyclic ether ring having one oxygen as a ring member;

Ring A is a five-membered heteroaryl ring containing at least one carbonring atom and up to four heteroatoms selected from N, O and S as ringmembers, wherein

-   -   Z¹ is N, O or S;    -   Z² and Z³ are independently CR^(z), N, NR^(z), O or S; and    -   Z⁴ and Z⁵ each independently represent C or N,        -   provided Z⁴ and Z⁵ are not both simultaneously N,        -   where each R^(z) is independently selected from H, halo,            C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl            containing one or two heteroatoms selected from N, O and S            as ring members, C₁₋₄ alkoxy, CN, CON(R⁴)₂ and C₁₋₄            haloalkyl, wherein the C₁₋₄ alkyl is optionally substituted            with one or two groups selected from —OR⁴, —N(R⁴)₂, COOR⁴,            CON(R⁴)₂, and a 5-6 membered heterocyclic ring containing            one or two heteroatoms selected from N, O and S as ring            members;

R⁴ at each occurrence is independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₆ cycloalkyl, phenyl, a 5-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, and 5-6membered heterocyclic ring containing one or two heteroatoms selectedfrom N, O and S as ring members are each optionally substituted with oneor two groups independently selected from halo, —OH, C₁₋₂ alkyl, and—O(C₁₋₂ alkyl);

-   -   and two R⁴ groups directly attached to the same nitrogen atom        can optionally be taken together to form a 4-6 membered        heterocycle optionally containing an additional heteroatom        selected from N, O and S as a ring member and optionally        substituted with one or two groups selected from halo, —OH, C₁₋₂        alkyl, and —O(C₁₋₂ alkyl);

Ar¹ and Ar² each represent phenyl or a 5-6 membered heteroaryl ringcontaining 1-3 heteroatoms selected from N, O and S as ring members, andare each independently substituted with up to three groups selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, —S(C₁₋₃ alkyl), —SO₂(C₁₋₃ alkyl), and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic ring system        wherein each Ar¹ and Ar² is optionally substituted by up to two        groups independently selected from halo, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, —S(C₁₋₃        alkyl), —SO₂(C₁₋₃ alkyl), and CN,    -   where L is selected from S, S═O, SO₂, O, C(R^(L))₂ and CF₂,    -   and each R^(L) is independently H or C₁₋₂ alkyl.

A particular aspect of Embodiment 1 is a compound of Embodiment 1a,which is a compound having this formula:

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is CR^(X1) or N, where R^(X1) is H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl,CN, COOH, or a 5-6 membered heteroaryl ring containing 1-4 heteroatomsselected from N, O and S as ring members and optionally substituted by1-2 groups selected from halo, hydroxy, amino, C₁₋₃ alkyl, C₁₋₃haloalkyl, and C₁₋₃ alkoxy;

X² is CR^(X2) or N, where R^(X2) is H, halo, C₁₋₆ alkyl or C₁₋₄haloalkyl;

X³ is CR^(X3) or N, where R^(X3) is H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

-   -   provided that X² is CR^(X2) if either or both of X¹ and X³        represent N;

R¹ is H, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₄ alkoxy;

Ring A is a five-membered heteroaryl ring containing at least one carbonring atom and up to four heteroatoms selected from N, O and S as ringmembers, wherein

-   -   Z¹ is N, O or S;    -   Z² and Z³ are independently CR^(z), N, NR^(z) O or S; and    -   Z⁴ and Z⁵ each independently represent C or N, provided Z⁴ and        Z⁵ are not both simultaneously N,    -   where each R^(z) is independently selected from H, halo, C₁₋₄        alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

R² and R³ are independently H or C₁₋₄ alkyl;

Ar¹ and Ar² each represent phenyl or a 5-6 membered heteroaryl ringcontaining 1-3 heteroatoms selected from N, O and S as ring members, andare each independently substituted with up to three groups selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄alkyne, and CN;

-   -   and Ar¹ and Ar² are optionally linked together by a bridge of        the formula —C(R^(L))₂-L- to form a tricyclic ring system        wherein each Ar¹ and Ar² is optionally substituted by up to two        groups independently selected from halo, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN,    -   where L is selected from S, S═O, SO₂, O, C(R^(L))₂ and CF₂,    -   and each R^(L) is independently H or C₁₋₂ alkyl.

Embodiment 2

A compound according to embodiment 1 or 1a, or a pharmaceuticallyacceptable salt thereof, wherein X¹ is CH.

Embodiment 3

A compound according to embodiment 1 or 1a or embodiment, 2 or apharmaceutically acceptable salt thereof, wherein X² is CH or N.

Embodiment 4

A compound according to any one of the preceding embodiments, or apharmaceutically acceptable salt thereof, wherein X³ is CH.

Embodiment 5

A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R² and R³ are both H.

Embodiment 6

A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein R¹ is H.

Embodiment 7

A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein Ring A is selectedfrom imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole,isothiazole, oxadiazole, thiadiazole, and tetrazole.

Embodiment 8

A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein Z⁵ is C.

Embodiment 9

A compound according to any of the preceding embodiments or apharmaceutically acceptable salt thereof, wherein Z⁴ is N.

Embodiment 10

A compound according to any one of the preceding embodiments, or apharmaceutically acceptable salt thereof, wherein Z³ is CR^(z) or N.

Embodiment 11

A compound of any of the preceding embodiments or a pharmaceuticallyacceptable salt thereof, wherein ring A is selected from imidazole,pyrazole, triazole and tetrazole.

Embodiment 12

A compound of any of the preceding embodiments, which is of the formula:

wherein Y represents a group selected from

wherein each R^(y) is independently selected from H, halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN,

or a pharmaceutically acceptable salt thereof. In these embodiments, Gis sometimes H. In other examples of these embodiments, G is selectedfrom —C(O)R, —C(O)—OR, —CH₂—O—C(O)R, and —CH₂—O—C(O)—OR; wherein R isC₁-C₄ alkyl, optionally substituted with one or two groups selected fromhalo, CN, —OH, amino, phenyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy.

Embodiment 13

A compound of embodiment 1 or 1a, which is selected from the compoundsin Table 1 and the pharmaceutically acceptable salts thereof.

Embodiment 14

A pharmaceutical composition comprising a compound of any of thepreceding embodiments or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable carriers.

Embodiment 15

A combination comprising a therapeutically effective amount of acompound according to any one of embodiments 1 to 13 or apharmaceutically acceptable salt thereof and one or more therapeuticallyactive co-agents.

Embodiment 16

A method of treating influenza, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound of any ofembodiments 1-13 or a pharmaceutically acceptable salt thereof.

Embodiment 17

A compound according to any one of embodiments 1 to 13 or apharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 18

A compound according to any one of embodiments 1 to 13 or apharmaceutically acceptable salt thereof, for use in the treatment ofinfluenza.

Embodiment 19

Use of a compound according to any one of embodiments 1 to 13 or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of influenza.

In some embodiments, the compound of Formula (I) is a compound of one ofthe following formulas (I-A) through (I-J):

In Formula (I-G), one of Z¹ and Z² is N, and the other is either 0 or S.In Formula (I-H), Z² and Z³ are independently N or CR^(z). Othervariables in Formulas (I-A) through (I-J) are as defined for Formula (I)above. In some embodiments, G in compounds of Formulas (I-A) through(I-J) is H. In other compounds of Formulas (I-A) through (I-J), G isselected from —C(O)R, —C(O)—OR, —CH₂—O—C(O)R, and —CH₂—O—C(O)—OR. Thecompounds of these embodiments can be used in the compositions,combinations, methods and uses of embodiments 14-19.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog ‘R—S’ system. When a compound is a pure enantiomer,the stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)—.

Depending on the choice of the starting materials and synthesisprocedures, the compounds can be present in the form of one of thepossible isomers or as mixtures thereof, for example as pure opticalisomers, or as isomer mixtures, such as racemates and diastereoisomermixtures, depending on the number of asymmetric carbon atoms. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, diasteriomeric mixtures and optically pureforms. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration unless specified. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration, unless otherwise specified. All tautomeric formsare also intended to be included.

In many cases, the compounds of the present invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. As used herein, the terms“salt” or “salts” refers to an acid addition or base addition salt of acompound of the invention. “Salts” include in particular “pharmaceuticalacceptable salts”. The term “pharmaceutically acceptable salts” refersto salts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Lists of additional suitable salts can be found,e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic or organic bases and can have inorganic or organiccounterions.

Inorganic counterions for such base salts include, for example, ammoniumsalts and metals from columns I to XII of the periodic table. In certainembodiments, the counterion is selected from sodium, potassium,ammonium, alkylammonium having one to four C1-C4 alkyl groups, calcium,magnesium, iron, silver, zinc, and copper; particularly suitable saltsinclude ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Suitable organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, tetrahydrofuran, toluene, chloroform, dichloromethane,methanol, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable.

Any formula given herein is also intended to represent unlabeled forms(i.e., compounds wherein all atoms are present at natural isotopicabundances, and not isotopically enriched) as well as isotopicallyenriched or labeled forms of the compounds. Isotopically enriched orlabeled compounds have structures depicted by the formulas given hereinexcept that at least one atom of the compound is replaced by an atomhaving an atomic mass or mass number different from the atomic mass orthe atomic mass distribution that occurs naturally. Examples of isotopesthat can be incorporated into enriched or labeled compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I. The invention includes variousisotopically labeled compounds as defined herein, for example those inwhich radioactive isotopes, such as ³H and ¹⁴C, or those in whichnon-radioactive isotopes, such as ²H and ¹³C, are present at levelssignificantly above the natural abundance for these isotopes. Theseisotopically labeled compounds are useful in metabolic studies (e.g.,with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H),detection or imaging techniques, such as positron emission tomography(PET) or single-photon emission computed tomography (SPECT) includingdrug or substrate tissue distribution assays, or in radioactivetreatment of patients. In particular, an ¹⁸F labeled compound may beparticularly desirable for PET or SPECT studies. Isotopically-labeledcompounds of formula (I) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d⁶-acetone, d⁶-DMSO, as well as solvates withnon-enriched solvents.

Compounds of the invention, i.e., compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart for use in a pharmaceutical composition for administration to ahuman subject (see, for example, Remington: The Science and Practice ofPharmacy, 22nd ed.). Except insofar as any conventional carrier isincompatible with the active ingredient, its use in the therapeutic orpharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response in asubject, for example, an amount sufficient to reduce of one or moresymptoms, alleviate conditions, slow or delay disease progression, orprevent a disease, etc. In one non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of a compound ofthe present invention that, when administered to a subject, is effectiveto reduce one or more symptoms associated with an influenza virusinfection, or to shorten the duration of the symptomatic stage of aninfluenza virus infection, or to slow the progression of an influenzavirus infection, or to reduce or stop the exacerbation of an underlyingcondition by an influenza virus infection.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to cause astatistically significant reduction in rate of replication orproliferation of a strain of orthomyxovirus.

As used herein, the term “subject” refers to an animal. Typically, thesubject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the development or progression of the disease or disorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess ofeither the (R)- or (S)-configuration; i.e., for optically activecompounds, it is often preferred to use one enantiomer to thesubstantial exclusion of the other enantiomer, so typically anenantiomeric purity of at least 95% is preferred. Substituents at atomswith unsaturated double bonds may, if possible, be present in cis-(Z)-or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof. ‘Substantially pure’ or‘substantially free of other isomers’ as used herein means the productcontains less than 5%, and preferably less than 2%, of other isomersrelative to the amount of the preferred isomer, by weight.

Resulting mixtures of isomers can typically be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Racemates of final products or intermediates can typically be resolvedinto the optical antipodes by known methods, e.g., by separation of thediastereomeric salts thereof, obtained with an optically active acid orbase, and liberating the optically active acidic or basic compound. Inparticular, a basic moiety may thus be employed to resolve the compoundsof the present invention into their optical antipodes, e.g., byfractional crystallization of a salt formed with an optically activeacid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaricacid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid orcamphor-10-sulfonic acid. Racemic products can also be resolved bychiral chromatography, e.g., high pressure liquid chromatography (HPLC)using a chiral stationary phase.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, orapharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition comprises at least two pharmaceuticallyacceptable excipients or carriers. Pharmaceutically acceptable carriersand other excipients are known to those of skill in the art, and may beselected, for example, from carriers and excipients used in approved(registered) formulated therapeutic agents that are administered viasimilar routes of administration. The pharmaceutical composition can beformulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,and the like. In addition, the pharmaceutical compositions of thepresent invention can be made up in a solid form (including withoutlimitation capsules, tablets, pills, granules, powders orsuppositories), or in a liquid form (including without limitationsolutions, suspensions or emulsions). The pharmaceutical compositionscan be subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifers and buffers, etc.

In one embodiment, the compounds of the invention are formulated fororal delivery. Typically, these pharmaceutical compositions are tabletsor gelatin capsules comprising the active ingredient (at least onecompound of Formula (I)) together with one or more excipients selectedfrom:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems may pertain to an inhalation or to anintranasal application that may be suitable for use to treat influenza,for example, and may contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives. They may be convenientlydelivered in the form of a dry powder (either alone, as a mixture, forexample a dry blend with lactose, or a mixed component particle, forexample with phospholipids) from a dry powder inhaler or an aerosolspray presentation from a pressurized container, pump, spray, atomizeror nebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula (I), in free form or in salt form, exhibitvaluable pharmacological properties, e.g. they inhibit or preventreplication of orthomyxovirus, as indicated by test data provided in thenext sections, and are therefore indicated for therapy or for use asresearch chemicals, e.g. as tool compounds such as for the study ofreplication of an orthomyxovirus, particularly Influenza A, Influenza Bor Influenza C. Accordingly, compounds of the invention are useful inthe treatment of an infection caused by an orthymyxovirus, particularlyInfluenza A, Influenza B or Influenza C, especially in human subjects.In some embodiments, the subject to be treated is a human having or atrisk of contracting an influenza viral infection. For example, subjectshaving pre-existing conditions such as asthma or COPD that can begreatly exacerbated by an influenza infection may be treated with themethods or compounds of the invention before exhibiting symptoms of aninfluenza infection, especially if they are at risk of contractinginfluenza due to close proximity to persons such as family members whohave or appear to have influenza. In other embodiments, the subject fortreatment by the methods and compositions of the invention is onediagnosed as having symptoms consistent with an influenza infection. Inother embodiments, the subject may be a human who has been tested withknown diagnostic methods such as a Rapid Influenza Diagnostic Test(RIDT) or Reverse Transcriptase PCT (RT-PCR) methods to detect thepresence of influenza virus, and found to be infected with influenza,regardless of the presence of typical influenza symptoms.

As a further embodiment, the present invention provides the use of acompound of formula (I) or any of the embodiments within the scope ofFormula (I) as described herein, in therapy. In particular, thecompounds are suitable for use to treat a subject having or atparticularly high risk for an orthomyxovirus viral infection, especiallyInfluenza A, Influenza B, or Influenza C.

In another embodiment, the invention provides a method of treating adisease which is caused by an orthomyxovirus, comprising administrationof a therapeutically effective amount of a compound of formula (I) orany of the embodiments within the scope of Formula (I) as describedherein to a subject in need of such treatment. In some embodiments, thecompound of formula (I) is administered orally. In a further embodiment,the disease is selected from Influenza A, Influenza B, and Influenza C.The method typically comprises administering an effective amount of acompound as described herein, or a pharmaceutical composition comprisingan effective amount of such compound, to a subject in need of suchtreatment. The compound may be administered by any suitable method suchas those described herein, and the administration may be repeated atintervals which may be selected by a treating physician. In someembodiments, the compound or pharmaceutical composition is administeredorally.

Thus, as a further embodiment, the present invention provides the use ofa compound of formula (I) or any of the embodiments of such compoundsdescribed herein for the manufacture of a medicament. In a particularembodiment, the medicament is for treatment of an orthomyxovirusinfection, especially Influenza A, Influenza B, or Influenza C.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more therapeuticco-agent(s). The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the co-agent(s).Suitable co-agents for use with the compounds of the invention includeantivirals active on influenza viruses, such as neuraminidase inhibitorsincluding oseltamivir, peramivir, zanamivir and laninamivir, laninamiviroctanoate, and adamantanes such as amantadine and rimantadine.Additional co-agents for use in these methods include an M2 proteininhibitor, a polymerase inhibitor, a PB2 inhibitor, favipiravir,fludase, ADS-8902, beraprost, Neugene®, ribavirin, CAS Reg. No.1422050-75-6, VX-787, Flu Mist Quadrivalent®, Fluarix® Quadrivalent,Fluzone® Quadrivalent, Flucelvax® and FluBloke.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic co-agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a viralinfection caused by an orthomyxovirus, particularly Influenza A,Influenza B or Influenza C. Products provided as a combined preparationinclude a composition comprising a compound of formula (I) and at leastone of the other therapeutic co-agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and at leastone other therapeutic co-agent(s) in separate form, e.g. in the form ofa kit for use to treat a subject by the methods described herein.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeuticco-agent(s). Suitable co-agents include antivirals active on influenzaviruses, such as neuraminidase inhibitors including oseltamivir,peramivir, zanamivir and laninamivir, and adamantanes such as amantadineand rimantadine. Optionally, the pharmaceutical composition may comprisea pharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). The other pharmaceutical composition maycontain one of the suitable co-agents. In one embodiment, the kitcomprises means for separately retaining said compositions, such as acontainer, divided bottle, or divided foil packet. An example of such akit is a blister pack, as typically used for the packaging of tablets,capsules and the like.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the therapeutic co-agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the therapeutic co-agent may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe therapeutic co-agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a viral infection caused by an orthomyxovirus, particularlyinfluenza, which may be Influenza A, Influenza B or Influenza C, whereinthe medicament is prepared for administration with a therapeuticco-agent. Typically in the methods of using the compounds of theinvention, the serotype of influenza is not identified before treatment.The invention also provides the use of therapeutic co-agent for treatinga disease or condition, wherein the medicament is administered with acompound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a viral infection caused by an orthomyxovirus,particularly Influenza A, Influenza B or Influenza C, wherein thecompound of formula (I) is prepared for administration with atherapeutic co-agent. The invention also provides another therapeuticco-agent for use in a method of treating a viral infection caused by anorthomyxovirus, particularly influenza, e.g., Influenza A, Influenza Bor Influenza C, wherein the therapeutic co-agent is prepared foradministration with a compound of formula (I). The invention alsoprovides a compound of formula (I) for use in a method of treating aviral infection caused by an orthomyxovirus, particularly Influenza A,Influenza B or Influenza C, wherein the compound of formula (I) isadministered with a therapeutic co-agent. The invention also provides atherapeutic co-agent for use in a method of treating a viral infectioncaused by an orthomyxovirus, particularly Influenza A, Influenza B orInfluenza C, wherein the a therapeutic co-agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a viral infection caused by an orthomyxovirus, particularlyinfluenza, e.g., Influenza A, Influenza B or Influenza C, wherein thepatient has previously (e.g. within 24 hours) been treated with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a viral infection caused by anorthomyxovirus, particularly Influenza A, Influenza B or Influenza C,wherein the patient has previously (e.g. within 24 hours) been treatedwith a compound of formula (I).

In one embodiment, the therapeutic co-agent is selected from antiviralspurported to be useful for treating infections caused by influenzaviruses, such as neuraminidase inhibitors including oseltamivir,peramivir, zanamivir and laninamivir, and adamantanes such as amantadineand rimantadine.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage containing about 1-1000 mg of active ingredient(s)for a human subject of about 50-70 kg, or about 1-500 mg, or about 1-250mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 0.1-50 mg/kg.

The invention further includes processes to make the compounds ofFormula (I) as disclosed herein, and any variant of the presentprocesses, in which an intermediate product obtainable at any stagethereof is used as starting material and the remaining steps are carriedout, or in which the starting materials are formed in situ under thereaction conditions, or in which the reaction components are used in theform of their salts or optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

A method to synthesize compounds of Formula (I-A) is depicted in SchemeA. The first step is to generate aldehyde A-2 from ester A-1 bytreatment with a reducing agent, such as DIBAL-H. A-2 then undergoescycloaddition upon treatment with amino alcohol A-3 in the presence ofammonium acetate and a 1,2-dicarbonyl species, such as glyoxal orbiacetal, to provide isoxazole A-4. The alcohol A-4 can be converted tothe corresponding mesylate A-5, with subsequent one step or two stepdeprotection of protecting groups P1 and P2 to give A-6. Treatment ofA-6 with a base, such as potassium or cesium carbonate, in an aproticsolvent, such as DMF or NMP, provides A-7. In similar fashion, anappropriately protected ester A-8 can be transformed to A-9.Alternatively, P1 and P2 can be removed together or stepwise fromintermediate A-4 to provide A-10, which can be treated under Mitsunobuconditions to provide A-7 as shown.

A method to synthesize compounds of Formula (I-B) is depicted in SchemeB. The first step is to condense amide B-1 with dimethyl acetalmethanamine B-2 to provide B-3. Treatment of B-3 with hydrazide B-4 in amixed solvent system consisting of, for example, water, butanol andacetic acid at elevated temperature gives B-5. The alcohol B-5 can beconverted to the corresponding mesylate B-6, with subsequent one step ortwo step deprotection of protecting groups P1 and P2 to give B-7.Treatment of B-7 with a base, such as potassium or cesium carbonate, inan aprotic solvent, such as DMF or NMP, provides B-8. In similar fashionan appropriately protected ester B-9 can be transformed to B-10.Alternatively, P1 and P2 can be removed together or stepwise fromintermediate B-5 to provide B-11 which can be treated under Mitsunobuconditions to provide B-8.

A method to synthesize compounds of Formula (I-C) is depicted in SchemeC. The first step is to couple acyl hydrazide C-1, conveniently preparedfrom the corresponding carboxylic acid, with dimethyl acetal methanamineC-2 to provide C-3. Treatment of C-3 with amine C-4 in a mixed solventsystem consisting of, for example, acetonitrile and acetic acid atelevated temperature gives C-5. Following the previously described(Scheme A & Scheme B) three step manipulation of mesylation,deprotection and treatment with a base, such as potassium or cesiumcarbonate, provides C-6. In similar fashion appropriately protectedintermediates C-7 can be transformed into C-8. Alternatively, asdescribed for similar intermediates in Scheme A and Scheme B, P1 and P2can be removed together or stepwise from intermediate C-5, and theresulting alcohol can be treated under Mitsunobu conditions to provideC-6.

A method to synthesize compounds of Formula (l-D) is depicted in SchemeD. The first step is to couple the carboxylic acid D-1 with amine D-2 toprovide amide D-3. Protection of the alcohol on D-3 with a silylatingagent such as, for example, TBDMS-CI or TBDPS-CI, provides intermediateD-4. Treatment of D-4 with PCI3 or phosgene provides D-5. Treatment withazide followed by removal of the silyl protecting group provides D-6.Following the previously described (Scheme A & Scheme B) three stepmanipulation of mesylation, deprotection and treatment with a base, suchas potassium or cesium carbonate, provides D-7. In similar fashionappropriately protected intermediates D-8 can be transformed into D-9.Alternatively, as described for similar intermediates in Scheme A andScheme B, P1 and P2 can be removed together or stepwise fromintermediate D-6, and the resulting alcohol can be treated underMitsunobu conditions to provide D-7.

A method to synthesize compounds of Formula (I-E) is depicted in SchemeE. The first step is to brominate ketone E-1 with a reagent such as, forexample, bromine in acetic acid, to provide E-2. Reduction of the ketonefollowed by protection with a silylating agent such as, for example,TBS-CI, provides E-3. Treatment of bromide E-3 with TosMIC(toluenesulfonylmethyl isocyanide) in the presence of a base such assodium hydride provides intermediate E-4. Combining E-4 with aldehydeE-5 in the presence of a base in a solvent such as, for example,methanol provides oxazole E-6. Removal of the silyl protecting groupprovides alcohol E-7. Following the previously described (Scheme A &Scheme B) three step manipulation of mesylation, deprotection andtreatment with a base, such as potassium or cesium carbonate, providesE-8. In similar fashion an appropriately protected intermediate E-9 canbe transformed into E-10.

Alternatively, as described for similar intermediates in Scheme A andScheme B, P1 and P2 can be removed together or stepwise fromintermediate E-7 and the resulting alcohol can be treated underMitsunobu conditions to provide E-8.

A method to synthesize compounds of Formula (I-F) is depicted in SchemeF. The first step is to couple aldehyde F-1 with toluenesulfinic acid inthe presence of TMS-Cl and formamide in a mixed solvent system such as,for example, toluene and acetonitrile, to provide F-2. Treatment withPOCl₃ in the presence of a base such as 2,6-lutidine in a solvent suchas THF then provides F-3. Treatment of F-3 with aldehyde F-4 in thepresence of a base such as potassium carbonate in a solvent such asmethanol provides oxazole F-5. Removal of the silyl protecting groupprovides alcohol F-6. Following the previously described (Scheme A &Scheme B) three step manipulation of mesylation, deprotection andtreatment with a base, such as potassium or cesium carbonate, providesF-7. In similar fashion, appropriately protected intermediates F-8 canbe transformed into F-9.

Alternatively, as described for similar intermediates in Scheme A andScheme B, P1 and P2 can be removed together or stepwise fromintermediate F-6 and the resulting alcohol can be treated underMitsunobu conditions to provide F-7.

A method to synthesize compounds of Formula (I-G) is depicted in SchemeG. The first step is to treat epoxide G-1 with acetonitrile under basicconditions to provide G-2. Treatment of G-2 with a base such as KOtAmyl(potassium tert-amyloxide) followed by addition of ester G-3 providesintermediate G-4. Removal of the silyl group followed by mesylationprovides intermediate G-5. Subsequent one step or two step deprotectionof protecting groups P1 and P2 to provides G-6. Treatment with a basesuch as potassium carbonate in a solvent such as DMF or NMP providesG-7. Reduction of the nitrile to aldehyde with a reducing agent such asDIBAL-H provides aldehyde G-8. Treatment of G-8 with hydroxylamine thenprovides a mixture of G-9 and G-10.

Alternatively, G-8 can be treated in a two step reaction sequence withreagents such as Lawesson's reagent followed by ammonia to give G-11, orammonia followed by Lawesson's reagent to give G-12. Treatment of G-11or G-12 with an oxidant such as hydrogen peroxide then provides G-13 andG-14, respectively.

In similar fashion an appropriately protected intermediate G-15 can betransformed into G-16.

A method to synthesize compounds of Formula (I-H) is depicted in SchemeH. The first step is to brominate H-1 with a reagent such as NBS andthen protect the —OH with a protecting group such as benzyl to provideH-2. Suzuki coupling with a 1,3,4-triazole boronic acid (orcorresponding boronate ester) then provides H-3. A related imidazole H-6can be prepared from ester H-4 by reduction of the ester to the aldehydeusing a reducing agent such as DIBAL-H to give H-5. Subsequent treatmentwith an ammonia source such as ammonium carbonate in the presence of a1,2-dicarbonyl species, such as glyoxal or biacetal, then provides H-6.A related tetrazole can be prepared from H-2 by a palladium-mediatedcyanation to give H-7 followed by treatment with an azide source such asTMS-azide to give H-8.

Treatment of intermediate H-3, H-6 or H-8 with hydrazine then providesintermediates H-9. Condensation of an aldehyde or ketone with H-9 thenprovides intermediates H-10. Alkylation with a biaryl bromide such asH-11 then provides H-12. Alternatively, treatment of H-10 with a biarylketone under reductive amination conditions provides H-12.

Using these synthesis schemes and the examples provided, the skilledperson can prepare the compounds of Formula (I).

EXAMPLES

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (about 20-133 mbar). The structure of final products,intermediates and starting materials is confirmed by standard analyticalmethods, e.g., microanalysis and spectroscopic characteristics, e.g.,MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art in view of the following examples.

Abbreviations

ATP adenosine 5′-triphosphate

Bn benzyl

BOC tertiary butyl carboxy

br broad

BSA bovine serum albumin

d doublet

dd doublet of doublets

DCM dichloromethane

DEAD diethyl azodicarboxylate

DBAD di-tert-butyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DIEA diethylisopropylamine

DME 1,4-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DTT dithiothreitol

EDTA ethylenediamine tetraacetic acid

ESI electrospray ionization

EtOAc ethyl acetate

FCC flash column chromatography

h hour(s)

HBTU1-[bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate(1-)3-oxide

HOBt 1-hydroxy-7-azabenzotriazole

HPLC high pressure liquid chromatography

IR infrared spectroscopy

LCMS liquid chromatography and mass spectrometry

MeOH methanol

MS mass spectrometry

MW microwave

m multiplet

min minutes

mL milliliter(s)

m/z mass to charge ratio

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NIS N-iodosuccinimide

NMP N-methyl pyrrolidinone

NMR nuclear magnetic resonance

ppm parts per million

PyBOP benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

rac racemic

rt room temperature

s singlet

SEM (2-(trimethylsilyl)ethoxy)methyl

t triplet

TBDMS t-butyldimethylsilyl

TBDPS t-butyldiphenylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

Tris.HCl aminotris(hydroxymethyl)methane hydrochloride

Example 1:6-Benzhydryl-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-oneIntermediate 1.1: 3-Nitro-1,1-diphenylpropan-2-ol

To a solution of 2,2-diphenylacetaldehyde (5.0 g, 26 mmol) innitromethane (27 mL) was added K₂CO₃ (11.3 g, 82.0 mmol). The suspensionwas stirred at room temperature for 30 minutes. The mixture was thenfiltered to remove solids and the filtrate was concentrated. The residuewas taken up in EtOAc (100 mL) and washed sequentially with water (100mL), brine (2×25 mL), dried (Na₂SO₄), filtered and concentrated. Silicagel column chromatography (EtOAc/Heptane) provided3-nitro-1,1-diphenylpropan-2-ol (5.6 g, colorless oil that became solidupon standing) in 85% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.27 (m,10H), 5.13 (dddd, J=9.3, 6.8, 5.2, 3.9 Hz, 1H), 4.46-4.34 (m, 2H), 3.99(d, J=9.3 Hz, 1H), 2.33 (d, J=3.8 Hz, 1H). MS m/z 228.2 (M+1).

Intermediate 1.2: 3-Amino-1,1-diphenylpropan-2-ol

To a solution of 3-nitro-1,1-diphenylpropan-2-ol (5.6 g, 22 mmol) inabsolute EtOH (73 mL) under a nitrogen atmosphere was added 10% Pd/C(2.3 g). The flask was evacuated and refilled with H₂ from a balloon(three times) and then stirred vigorously at room temperature under aballoon of H₂ for 24 hours. The reaction flask was then purged withnitrogen and the mixture was filtered through celite. The filtrate wasconcentrated to give 3-amino-1,1-diphenylpropan-2-ol (4.9 g, colorlessoil) in 100% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.10 (m, 10H), 4.28(ddd, J=9.0, 7.8, 3.1 Hz, 1H), 3.89 (d, J=9.0 Hz, 1H), 2.75 (ddd,J=12.9, 3.1, 1.7 Hz, 1H), 2.54 (ddd, J=12.9, 7.9, 1.0 Hz, 1H).

Intermediate 1.3:5-(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbaldehyde

A solution of DIBAL-H (1.0 M in toluene, 4.9 mL, 4.9 mmol) was addeddropwise to a solution of ethyl5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate(1.0 g, 2.5 mmol: see US 2015/0072982 A1) in THF (25 mL) at −78° C. Thereaction was stirred at −78° C. for 20 min and then quenched at the sametemperature by the dropwise addition of MeOH (3 mL). The cold bath wasremoved and the reaction was diluted with EtOAc and a saturated aqueoussolution of Rochelle's salt. The layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated. Silica gelcolumn chromatography (EtOAc/Heptane) provided5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbaldehyde(0.51 g, yellow oil that solidified upon standing) in 57% yield. ¹H NMR(400 MHz, CDCl₃) δ 10.37 (s, 1H), 7.67 (s, 1H), 7.46-7.31 (m, 5H), 5.34(s, 2H), 5.30 (s, 2H), 3.54-3.45 (m, 2H), 0.88-0.81 (m, 2H), −0.01 (d,J=7.3 Hz, 9H). MS m/z 361.3 (M+1).

Intermediate 1.4:5-(Benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one

Ammonium acetate (75 mg, 0.97 mmol) and glyoxal (40% in water, 0.11 mL,0.97 mmol) were added to a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbaldehyde (350 mg, 0.97 mmol) and3-amino-1,1-diphenylpropan-2-ol (110 mg, 0.48 mmol) in MeOH (2 mL). Themixture was heated at reflux for 2 hours and then cooled to roomtemperature. The reaction was diluted with EtOAc and washed with dilutebrine. The organic layer was dried (Na₂SO₄), filtered and concentratedto give crude5-(benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-onewhich was used without further purification. MS m/z 609.3 (M+1).

Intermediate 1.5:3-(2-(5-(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

Methanesulfonyl chloride (0.094 mL, 1.2 mmol) was added dropwise to asolution of crude5-(benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-oneand Et₃N (0.20 mL, 1.5 mmol) in DCM (24 mL) at 0° C. The mixture wasstirred at the same temperature for 30 min and then quenched with water.The layers were separated and the aqueous layer was extracted with DCM.The combined organic extracts were washed with brine, filtered andconcentrated. Silica gel column chromatography (EtOAc/Heptane) provided34245-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate (0.13 g, yellow oil) in 40% yield over two steps. MSm/z 687.4 (M+1).

Intermediate 1.6:3-(2-(5-Hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

10% Pd/C (21 mg) was added to a solution of3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate (0.13 g, 0.20 mmol) in MeOH (10 mL) under nitrogen atroom temperature. The flask was then evacuated and refilled with H₂ froma balloon (three times) and then stirred vigorously under a balloonatmosphere of H₂ for 30 min. The reaction flask was then purged withnitrogen and the mixture was filtered through celite. The filtrate wasconcentrated to give crude3-(2-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z597.2 (M+1).

Intermediate 1.7:3-(2-(5-Hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

Crude3-(2-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate was dissolved in TFA (4 mL) and stirred at roomtemperature for 2 hours. The reaction was then concentrated. The residuewas taken up in toluene and concentrated again to give crude3-(2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z467.2 (M+1).

Example 1:6-Benzhydryl-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one

K₂CO₃ (81 mg, 0.59 mmol) was added to a solution of crude3-(2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate in DMF (2 mL). The mixture was stirred at roomtemperature for 12 hours and then filtered to remove solids. Thefiltrate was purified by reverse phase HPLC. Product fractions werecombined, frozen and lyophilized to afford a TFA salt of6-benzhydryl-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one(21 mg, 0.043 mmol, white solid) in 22% yield over three steps. ¹H NMR(400 MHz, DMSO-d₆) δ 7.72-7.65 (m, 1H), 7.58 (s, 1H), 7.46 (d, J=7.3 Hz,2H), 7.41-7.32 (m, 3H), 7.31-7.25 (m, 1H), 7.16 (dddd, J=19.6, 6.7, 5.4,1.6 Hz, 5H), 5.89 (dd, J=11.4, 4.0 Hz, 1H), 4.73 (dd, J=14.1, 4.3 Hz,1H), 4.35 (d, J=14.1 Hz, 1H), 4.24 (d, J=11.4 Hz, 1H). MS m/z 371.2(M+1).

Example 2.6-(bis(3-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

This compound was made by the same process used to make Example 1.

MS m/z 406.9 (M+1).

Example 3.6-benzhydryl-11-hydroxy-5,6-dihydro-10H-[1,2,4]triazolo[5′,1′:3,4]pyrazino[1,2-b]pyridazin-10-oneIntermediate 3.1:5-(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamide

Triethylamine (0.11 mL, 0.80 mmol) was added to a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylicacid (200 mg, 0.53 mmol: see US 2015/0072982 A1) in DMF (4 mL) at 0° C.Ethyl chloroformate (0.061 mL, 0.64 mmol) was then added and theresulting mixture was stirred at 0° C. for 20 min. A solution of aqueousNH₄OH (30%, 1.5 mL, 11.6 mmol) was then added dropwise. The mixture wasstirred at 0° C. for 30 min and then diluted with water and extractedwith EtOAc (3 times). The combined organic extracts were washedsequentially with water, brine and then dried (Na₂SO₄), filtered andconcentrated to give crude5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamidewhich was used without further purification. MS m/z 376.3 (M+1).

Intermediate 3.2:(E)-5-(Benzyloxy)-N-((dimethylamino)methylene)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamide

A mixture of crude5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamide(0.2 g, 0.53 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) washeated at 100° C. for 1.5 hours. The solution was then cooled to roomtemperature and concentrated to give crude(E)-5-(benzyloxy)-N-((dimethylamino)methylene)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamidewhich was used without further purification.

Intermediate 3.3: 3-Hydrazinyl-1,1-diphenylpropan-2-ol

Hydrazine (0.33 mL, 10.5 mmol) was added to a solution of2-benzhydryloxirane (220 mg, 1.05 mmol: see Zhang, S.; Zhen, J.; Reith,Maarten E. A.; Dutta, A. K. J. Med. Chem. 2005, 48, 4962-4971) inethanol (10.5 mL) in a microwave vial. The vial was capped and themixture was heated in the microwave at 100° C. for 10 minutes. Thereaction mixture was concentrated and the residue was taken up in EtOAcand washed sequentially with water and brine. The organic layer was thendried (Na₂SO₄), filtered and concentrated to give crude3-hydrazinyl-1,1-diphenylpropan-2-ol which was used without furtherpurification. MS m/z 243.3 (M+1).

Intermediate 3.4:5-(Benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-1,2,4-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one

A solution of crude 3-hydrazinyl-1,1-diphenylpropan-2-ol (257 mg, 1.06mmol) in acetic acid (15 mL) was added to crude(E)-5-(benzyloxy)-N-((dimethylamino)methylene)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxamide(229 mg, 0.531 mmol). The mixture was heated to 90° C. for 5 minutes andthen cooled to room temperature. EtOAc was added and the mixture waswashed sequentially with water, saturated aqueous NaHCO₃, and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. Silica gelcolumn chromatography (0-10% MeOH in EtOAc) provided5-(benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-1,2,4-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(220 mg, colorless oil) in 68% yield. MS m/z 610.4 (M+1).

Intermediate 3.5:3-(5-(5-(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

Methanesulfonyl chloride (0.042 mL, 0.54 mmol) was added dropwise to asolution of5-(benzyloxy)-3-(1-(2-hydroxy-3,3-diphenylpropyl)-1H-1,2,4-triazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(220 mg, 0.36 mmol) and triethylamine (0.10 mL, 0.72 mmol) in DCM (24mL) at 0° C. The mixture was stirred at 0° C. for 30 min and thereaction was then quenched with water. The layers were separated and theaqueous layer was extracted with DCM. The combined DCM layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated to givecrude3-(5-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate which was used without further purification. MS m/z688.3 (M+1).

Intermediate 3.6:3-(5-(5-Hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

10% Pd/C (38 mg) was added to a solution of crude3-(5-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate (0.25 g, 0.36 mmol) in MeOH (36 mL) under nitrogen atroom temperature. The flask was then evacuated and refilled with H₂ froma balloon (three times) and then stirred vigorously under a balloonatmosphere of H₂ for 30 min. The reaction flask was then purged withnitrogen and the mixture was filtered through celite. The filtrate wasconcentrated to give crude3-(5-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z598.3 (M+1).

Intermediate 3.7:3-(5-(5-Hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate

Crude3-(5-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate (0.22 g, 0.36 mmol) was dissolved in TFA (4 mL) andstirred at 40° C. for 30 min. The reaction was then concentrated. Theresidue was taken up in toluene and concentrated again to give crude3-(5-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z468.2 (M+1).

Example 3: Preparation of6-benzhydryl-11-hydroxy-5,6-dihydro-10H-[1,2,4]triazolo[5′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

K₂CO₃ (150 mg, 1.08 mmol) was added to a solution of crude3-(5-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-1,2,4-triazol-1-yl)-1,1-diphenylpropan-2-ylmethanesulfonate (169 mg, 0.36 mmol) in DMF (3.6 mL). The mixture wasstirred at room temperature for 12 hours and then filtered to removesolids. The filtrate was purified by reverse phase HPLC. Productfractions were combined, frozen and lyophilized to afford a TFA salt of6-benzhydryl-11-hydroxy-5,6-dihydro-10H-[1,2,4]triazolo[5′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one(34 mg, 0.069 mmol, yellow solid) in 19% yield over four steps. ¹H NMR(400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.46-7.41 (m, 2H), 7.39-7.25 (m, 4H),7.23-7.09 (m, 5H), 5.92 (ddd, J=11.8, 4.3, 1.2 Hz, 1H), 4.91 (dd,J=13.9, 4.3 Hz, 1H), 4.26-4.20 (m, 1H), 3.95 (d, J=11.6 Hz, 1H). MS m/z372.3 (M+1).

Example 4: Preparation of(S)-6-Benzhydryl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-oneIntermediate 4.1: (S)-tert-Butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate

Ammonium acetate (189 mg, 2.45 mmol) and a solution of glyoxal (40% inwater, 0.28 mL, 2.45 mmol) were added to a solution of3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (564 mg, 2.45 mmol: US2015/0202208 A1) and (S)-tert-butyl(3-amino-1,1-diphenylpropan-2-yl)carbamate (400 mg, 1.23 mmol: US2012/0022251 A1) in MeOH (6 mL). The mixture was then heated at refluxfor 1 hour. Additional ammonium acetate (95 mg, 1.2 mmol) and glyoxal(40% in water, 0.14 mL, 1.2 mmol) were added and the solution was heatedat reflux for another 30 min. The mixture was then cooled to roomtemperature and diluted with EtOAc and water. The layers were separatedand the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered andconcentrated. Silica gel column chromatography (0-10% MeOH in EtOAc)provided (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(270 mg, yellow oil) in 38% yield. MS m/z 578.4 (M+1).

Intermediate 4.2:(S)-2-(1-(2-amino-3,3-diphenylpropyl)-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-one

TFA (3.6 mL) was added to a solution of (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(270 mg, 0.47 mmol) in DCM (12 mL) at room temperature. The solution wasstirred for 1 hour and then concentrated in vacuo to give crude(S)-2-(1-(2-amino-3,3-diphenylpropyl)-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-onewhich was used without further purification. MS m/z 478.3 (M+1).

Intermediate 4.3:(S)-6-benzhydryl-11-(benzyloxy)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Acetic acid (12 mL) was added to a solution of crude(S)-2-(1-(2-amino-3,3-diphenylpropyl)-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-one(223 mg, 0.47 mmol) in ethanol (24 mL). The mixture was heated at 80° C.for 1 hour. The reaction was cooled to room temperature and concentratedto give crude(S)-6-benzhydryl-11-(benzyloxy)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-onewhich was used without further purification. MS m/z 460.3 (M+1).

Example 4:(S)-6-Benzhydryl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

TFA (10 mL) was added to crude(S)-6-benzhydryl-11-(benzyloxy)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(215 mg, 0.47 mmol) in a microwave vial. The vial was capped and heatedin the microwave at 90° C. for 10 min. The reaction was thenconcentrated. The residue was taken up in DMSO and purified by reversephase HPLC. Product fractions were combined, frozen and lyophilized toafford a TFA salt of(S)-6-benzhydryl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(63 mg, 0.13 mmol, yellow solid) in 28% yield over three steps. ¹H NMR(400 MHz, DMSO-d₆) δ 7.72 (d, J=1.7 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H),7.51-7.45 (m, 2H), 7.44-7.36 (m, 2H), 7.35-7.10 (m, 7H), 5.92 (d, J=7.2Hz, 1H), 5.82 (dd, J=11.4, 3.7 Hz, 1H), 4.66 (dd, J=14.0, 4.1 Hz, 1H),4.34-4.27 (m, 1H), 4.19 (d, J=11.8 Hz, 1H). MS m/z 370.3 (M+1).

Example 5: Preparation of(S)-6-Benzhydryl-3-chloro-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-oneIntermediate 5.1:(S)-6-Benzhydryl-11-(benzyloxy)-3-chloro-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one

Palau'Chlor (24 mg, 0.11 mmol: Baran, et al., J. Am. Chem. Soc. 136(19),6908-11 (2014)) was added to a solution of crude Intermediate 4.3 (43mg, 0.094 mmol) in chloroform (0.9 mL) at RT. The mixture was stirred atRT for 20 min and then concentrated in vacuo. Silica gel chromatography(0-10% MeOH in EtOAc) provided(S)-6-benzhydryl-11-(benzyloxy)-3-chloro-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one (18 mg, yellow oil) in 39% yield. ¹H NMR (400 MHz,CDCl3) δ 7.69-7.64 (m, 2H), 7.40-7.27 (m, 7H), 7.20 (s, 1H), 7.12 (dt,J=7.5, 2.5 Hz, 5H), 6.93-6.86 (m, 2H), 6.48 (d, J=7.6 Hz, 1H), 5.81 (d,J=7.5 Hz, 1H), 5.50 (d, J=10.4 Hz, 1H), 5.37 (d, J=10.5 Hz, 1H), 4.61(ddd, J=11.4, 3.6, 1.4 Hz, 1H), 4.10-4.05 (m, 1H), 3.75 (s, 4H), 3.52(d, J=11.3 Hz, 1H). MS m/z 494.3 (M+1).

Example 5:(S)-6-Benzhydryl-3-chloro-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one

A solution of(S)-6-benzhydryl-11-(benzyloxy)-3-chloro-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one(18 mg, 0.036 mmol) in trifluoroacetic acid (3 mL) was heated in themicrowave at 90° C. for 10 min. The reaction was then concentrated. Theresidue was taken up in DMSO and purified by reverse phase HPLC. Productfractions were combined, frozen and lyophilized to afford a TFA salt of(S)-6-benzhydryl-3-chloro-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one(7 mg, 0.013 mmol, yellow solid) in 37% yield. ¹H NMR (400 MHz, DMSO-d6)δ 7.51 (s, 1H), 7.49-7.44 (m, 2H), 7.44-7.36 (m, 2H), 7.35-7.25 (m, 4H),7.24-7.13 (m, 3H), 5.94 (d, J=7.3 Hz, 1H), 5.86 (dd, J=11.7, 3.6 Hz,1H), 4.51 (dd, J=13.6, 3.8 Hz, 1H), 4.02 (d, J=11.6 Hz, 1H), 3.95 (dd,J=13.7, 1.2 Hz, 1H). MS m/z 404.2 (M+1).

Example 6.6-benzhydryl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

Intermediate 6.1: 2-(1H-imidazol-2-yl)-3-methoxy-4H-pyran-4-one

To 3-methoxy-4-oxo-4H-pyran-2-carbaldehyde (5.0 g, 32.4 mmol) in MeOH(50 mL) was added oxalaldehyde (40%, 9.41 mL, 64.9 mmol) and NH₄OAc(10.00 g, 130 mmol). The reaction was sealed and heated at 80° C. for 1hr. The mixture was cooled and concentrated. The residue was purified onSiO₂ (EtOAc in heptane 10% to 100%) to give product (3.21 g, 51%). MSm/z 193.1 (M+1).

Intermediate 6.2:1-benzyl-2-(1H-imidazol-2-yl)-3-methoxypyridin-4(1H)-one

To 2-(1H-imidazol-2-yl)-3-methoxy-4H-pyran-4-one (3.1 g, 16.13 mmol) inEtOH (30 mL) was added HOAc (4 mL) and phenylmethanamine (8.64 g, 81mmol). The reaction was sealed and heated at 100° C. for 20 min. Themixture was cooled and concentrated. The residue was purified on SiO₂(EtOAc in heptane 10% to 100%) to give product (3.88 g, 86%). MS m/z282.3 (M+1).

Intermediate 6.3: tert-butyl2-(1-benzyl-3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate

To 1-benzyl-2-(1H-imidazol-2-yl)-3-methoxypyridin-4(1H)-one (3.2 g,11.38 mmol) in ACN (30 mL) was added Cs₂CO₃ (7.41 g, 22.75 mmol) anddi-tert-butyl dicarbonate (4.97 g, 22.75 mmol). The reaction was sealedand heated at 60° C. for three hours. The mixture was cooled and dilutedwith EtOAC (100 mL). The mixture was then washed with water (50 mL) andbrine (50 mL). The organic was then dried (Na₂SO₄) and concentrated. Theresidue was purified on SiO₂ (EtOAc in heptane 10% to 100%) to giveproduct (3.68 g, 85%). MS m/z 382.3 (M+1).

Intermediate 6.4: tert-butyl2-(3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate

To tert-butyl2-(1-benzyl-3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate(400 mg, 1.049 mmol) in MeOH (10 mL) was added palladium on carbon (10%,400 mg, 0.376 mmol). The reaction was purged with hydrogen and stirredunder hydrogen for six hours. The mixture was then purged with nitrogenand filtered through celite and washed with MeOH. The filtrate wasconcentrated to give crude product. MS m/z 282.3 (M+1).

Intermediate 6.5: tert-butyl2-(1-amino-3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate

To tert-butyl2-(3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate(300 mg, 1.030 mmol) in DMF (3 mL) was added Cs₂CO₃ (403 mg, 1.236mmol). The mixture was stirred for 15 minutes andO-(2,4-dinitrophenyl)hydroxylamine (246 mg, 1.236 mmol) was then added.The reaction was stirred for one hour. The mixture was then diluted withwater (20 mL) and extracted with IPA in DCM (15%, 3×30 mL). The organicwas then dried (Na₂SO₄) and concentrated to give crude product. MS m/z307.2 (M+1).

Intermediate 6.6:1-amino-2-(1H-imidazol-2-yl)-3-methoxypyridin-4(1H)-one

To tert-butyl2-(1-amino-3-methoxy-4-oxo-1,4-dihydropyridin-2-yl)-1H-imidazole-1-carboxylate(300 mg, 0.979 mmol) in DCM (3 mL) was added TFA (4 mL). The reactionwas stirred for 20 minutes and then concentrated to give crude product.MS m/z 207.2 (M+1).

Intermediate 6.7:11-methoxy-5H-imidazo[1,2-f]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To 1-amino-2-(1H-imidazol-2-yl)-3-methoxypyridin-4(1H)-one (200 mg,0.970 mmol) in MeOH (3 mL) was added aqueous formaldehyde (30%, 291 mg,2.91 mmol). The reaction was sealed and heated at 55° C. for two hours.The mixture was cooled and concentrated. The residue was purified onSiO2 (MeOH in DCM 0% to 10%) to give product (156 mg, 73%). MS m/z 219.3(M+1).

Intermediate 6.8:6-benzhydryl-11-methoxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To 11-methoxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(25 mg, 0.115 mmol) in DMF (1 mL) was added (bromomethylene)dibenzene(56.6 mg, 0.229 mmol) and sodium hydride (60%, 9.16 mg, 0.229 mmol). Thereaction was stirred for 20 minutes. The mixture was diluted with water(5 mL) and extracted with IPA in DCM (15%, 3×10 mL). The organic wasdried (Na₂SO₄) and concentrated. The residue was purified on SiO₂ (MeOHin DCM 0% to 10%) to give product (30 mg, 68%). MS m/z 385.2 (M+1).

Example 6.6-benzhydryl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To6-benzhydryl-11-methoxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(20 mg, 0.052 mmol) in DMF (2 mL) was added BF₃-Et₂O (1 M in DCM, 0.156mL, 0.156 mmol) and LiBr (45.2 mg, 0.520 mmol). The reaction was sealedand heated at 100° C. for 60 minutes. The mixture was cooled andpurified by HPLC to give product (11 mg, 56%). MS m/z 371.3 (M+1).

¹H NMR (500 MHz, DMSO-d6) δ ppm 7.7 (s, 1H), 7.59 (s, 1H), 7.57 (m, 2H),7.52 (d, J=7.6 Hz, 1H), 7.46 (m, 2H), 7.4 (m, 1H), 7.23-7.3 (m, 5H),5.88 (d, J=7.6 Hz, 1H), 5.66 (dd, J=10 Hz, 2H), 5.14 (s, 1H).

Example 7.(S)-6-benzhydryl-3-bromo-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1: (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate

Added ammonium acetate (224 mg, 2.91 mmol) to a solution of3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (670 mg, 2.91 mmol),(S)-tert-butyl (3-amino-1,1-diphenylpropan-2-yl) carbamate (500 mg,1.455 mmol) (US 2012/0022251 A1)) and glyoxal (0.332 mL, 2.91 mmol) inMeOH (Volume: 9 mL) at RT. The mixture was then heated at reflux for 1Hin heating block. LC-MS shows formation of desired product beside someside product. Still saw unreacted amine. Added again 1 eq each ofammonium acetate and glyoxal and continue heating for another 1-2H.Reaction was complete by LC-MS. The reaction was cooled to RT anddiluted with EtOAc and water. The layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic extracts werewashed with brine, dried over Na2SO4, filtered and concentrated invacuo. The crude was purified by silica gel chromatography using 0-100%EtOAc (contains 10% MeOH)/Heptane to give (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamateas a light yellow foamy solid.

(840 mg, 1.454 mmol, 50.0% yield). LCMS: MH⁺578.2, 0.81 min.

Step 2: (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-bromo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate

To a solution of (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(430 mg, 0.744 mmol) in DCM (Volume: 10 mL) was added NBS (159 mg, 0.893mmol) and stirred at RT/1H. Reaction was complete by LC-MS. Reactionmixture was partitioned between DCM and water. The DCM layer wasseparated, washed with brine, dried over sodium sulfate, filtered andevaporated. The crude was purified by silica gel chromatography using0-100% EtOAc (contains 10% MeOH)/Heptane to give (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-bromo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamateas a yellow foamy solid, (360 mg, 0.548 mmol, 73.7% yield). LCMS:MH⁺655.9, 0.98 min.

Step 3:(S)-2-(1-(2-amino-3,3-diphenylpropyl)-5-bromo-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-one

To (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-bromo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(360 mg, 0.548 mmol) in DCM (1 ml) was added 40% TFA/DCM (4 mL, 20.77mmol) solution. Stirred at RT for 1 h. The reaction was complete byLC-MS. The reaction mixture was concentrated in vacuo and azeotrope withtoluene to obtain crude(S)-2-(1-(2-amino-3,3-diphenylpropyl)-5-bromo-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-one,(305 mg, 0.548 mmol, 100% yield). LCMS: MH⁺556.0, 0.78 min.

Proceed to the next step without further purification.

Step 4:(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

The crude(S)-2-(1-(2-amino-3,3-diphenylpropyl)-5-bromo-1H-imidazol-2-yl)-3-(benzyloxy)-4H-pyran-4-one(305 mg, 0.548 mmol) from step 3 was taken in Ethanol (6 ml) and aceticacid (3 ml). The mixture was then heated at 80° C. for 1H in heatingblock. The reaction was complete by LC-MS. The reaction mixture wasconcentrated in vacuo and the crude was purified by silica gelchromatography using 0-100% EtOAc (contains 10% MeOH)/Heptane to give(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-oneas a light yellow solid, (205 mg, 0.381 mmol, 69.4% yield). LCMS:MH⁺538.0, 0.81 min.

Step 5:(S)-6-benzhydryl-3-bromo-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(8 mg, 0.015 mmol) was added trifluoroacetic acid (0.5 ml). The solutionwas then heated at 90° C. for 15 min in microwave. The reaction wascomplete by LC-MS. The reaction was concentrated in vacuo and azeotropewith toluene. The crude was purified by Prep HPLC to obtain(S)-6-benzhydryl-3-bromo-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-oneas a TFA salt, (5.8 mg, 10.31 μmol, 69.4% yield). LCMS (m/z): 448.0(MH⁺), 0.71 min, 1H NMR (400 MHz, CD₃OD) δ ppm 7.46 (s, 1H) 7.43 (d,J=4.35 Hz, 3H) 7.35 (dq, J=8.76, 4.17 Hz, 1H) 7.30 (d, J=7.24 Hz, 1H)7.17-7.26 (m, 4H) 6.18 (d, J=7.14 Hz, 1H) 5.71 (dd, J=11.52, 2.91 Hz,1H) 4.45 (dd, J=13.79, 3.86 Hz, 1H) 4.28 (d, J=12.91 Hz, 1H) 4.04 (d,J=11.54 Hz, 1H).

Example 8:(S)-6-benzhydryl-3-cyclopropyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-3-cyclopropyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(40 mg, 0.074 mmol) (see example 7 step 4 for synthesis) in Toluene(Volume: 1, Ratio: 10.00) and Water (Volume: 0.1 mL, Ratio: 1.000) wasadded potassium cyclopropyltrifluoroborate (33.0 mg, 0.223 mmol),Di(1-adamantyl)-n-butylphosphine (5.33 mg, 0.015 mmol), cesium carbonate(121 mg, 0.371 mmol) and palladium(II) acetate (1.668 mg, 7.43 μmol).The reaction mixture was heated in heating block at 100° C./ON. Thereaction was 80% complete by LC-MS. The reaction was stopped andconcentrated on rotovap. The crude was partitioned between EtOAc andwater. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic extracts were washed with brine, driedover Na2SO4, filtered and concentrated in vacuo. The crude was purifiedby silica gel chromatography using 0-10% MeOH/DCM to give(S)-6-benzhydryl-11-(benzyloxy)-3-cyclopropyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,(23 mg, 0.046 mmol, 62.0% yield). LCMS: MH⁺500.3, 0.74 min.

Step 2:(S)-6-benzhydryl-3-cyclopropyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To(S)-6-benzhydryl-11-(benzyloxy)-3-cyclopropyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(23 mg, 0.046 mmol) was added trifluoroacetic acid (1 ml). The solutionwas then heated at 90° C. for 15 min in microwave. The reaction wascomplete by LC-MS. The reaction was concentrated in vacuo and azeotropewith toluene. The crude was purified by Prep HPLC to obtain(S)-6-benzhydryl-3-cyclopropyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-oneas a TFA salt, (6.5 mg, 0.012 mmol, 26.7% yield). LCMS (m/z): 410.3(MH⁺), 0.66 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.40-7.56 (m, 4H)7.29-7.40 (m, 2H) 7.13-7.26 (m, 5H) 6.03 (d, J=7.24 Hz, 1H) 5.58-5.81(m, 1H) 4.45-4.70 (m, 2H) 4.12 (d, J=11.69 Hz, 1H) 1.33-1.56 (m, 1H)0.75-0.98 (m, 2H) 0.60-0.71 (m, 1H) 0.32-0.43 (m, 1H)

Example 9:(S)-6-benzhydryl-3-ethyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-3-vinyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(30 mg, 0.056 mmol) (see example #1 for synthesis) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (17.16 mg, 0.111 mmol)in DME (Volume: 1.5 mL) and sodium carbonate (200 μL, 0.400 mmol) wasadded PdCl2(dppf). CH2Cl2 adduct (4.55 mg, 5.57 μmol). Reaction mixturewas heated in microwave at 110° C./15 min. Reaction was complete byLC-MS with major mass observed due to desired product. Reaction mixturewas partitioned between EtOAc and water. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated to givecrude(S)-6-benzhydryl-11-(benzyloxy)-3-vinyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,(27 mg, 0.056 mmol, 100% yield). LCMS: MH⁺ 486.3, 0.75 min.

Proceed for next step without purification.

Step 2:(S)-6-benzhydryl-11-(benzyloxy)-3-ethyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Added 10% Pd—C(10.96 mg, 10.30 μmol) to a solution of crude(S)-6-benzhydryl-11-(benzyloxy)-3-vinyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,(25 mg, 0.051 mmol) in MeOH (Volume: 5 mL) at RT under a nitrogenatmosphere. The flask was then evacuated and refilled with hydrogen froma balloon (3 times) and stirred under a balloon of hydrogen for 1 hour.LCMS showed complete reaction.

The reaction was filtered through a plug of celite (washed with MeOH)and the filtrate was concentrated in vacuo to give crude(S)-6-benzhydryl-11-(benzyloxy)-3-ethyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,LCMS: MH⁺ 488.3, 0.72 min.

Step 3:(S)-6-benzhydryl-3-ethyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-a]pyrazin-10(6H)-one

To crude(S)-6-benzhydryl-11-(benzyloxy)-3-ethyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one(25 mg, 0.051 mmol) was added trifluoroacetic acid (1 ml). The solutionwas then heated at 90° C. for 15 min in microwave. The reaction wasconcentrated in vacuo and azeotrope with toluene. The crude was purifiedby Prep HPLC to obtain(S)-6-benzhydryl-3-ethyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-oneas a TFA salt, (1.25 mg, 2.23 μmol I, 4.5% yield). LCMS (m/z): 398.3(MH⁺), 0.64 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.40-7.48 (m, 5H) 7.36(td, J=8.57, 4.28 Hz, 2H) 7.16-7.24 (m, 5H) 6.03 (d, J=7.19 Hz, 1H)5.63-5.75 (m, 1H) 4.52 (dd, J=14.01, 3.89 Hz, 1H) 4.32 (d, J=14.57 Hz,1H) 4.09 (d, J=11.54 Hz, 1H) 2.24-2.48 (m, 3H) 1.04-1.16 (m, 3H)

Example 10.6-(bis(4-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one

Synthesized by the method of Example 1. LCMS (m/z): 439.3 (MH⁺), 0.75min, 1H NMR (400 MHz, CD₃OD) δ ppm 7.58 (d, J=1.47 Hz, 1H) 7.54 (d,J=1.47 Hz, 1H) 7.50 (s, 1H) 7.40 (s, 4H) 7.12-7.21 (m, 4H) 5.81 (dd,J=11.15, 3.37 Hz, 1H) 4.75 (dd, J=14.26, 4.28 Hz, 1H) 4.50 (d, J=13.79Hz, 1H) 4.28 (d, J=11.20 Hz, 1H)

Example 11.6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one

Synthesized by the method of Example 1. LCMS (m/z): 439.3 (MH⁺), 0.74min, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 (d, J=1.66 Hz, 1H) 7.61 (d,J=1.61 Hz, 1H) 7.52 (s, 1H) 7.48 (s, 1H) 7.32-7.44 (m, 3H) 7.14-7.24 (m,3H) 7.07-7.13 (m, 1H) 5.89 (dd, J=11.05, 3.37 Hz, 1H) 4.79 (dd, J=14.35,4.28 Hz, 1H) 4.57 (d, J=13.69 Hz, 1H) 4.36 (d, J=11.10 Hz, 1H)

Example 12.6-(bis(4-fluorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one

Synthesized by the method of Example 1. LCMS (m/z): 407.3 (MH⁺), 0.63min, 1H NMR (400 MHz, CD3OD) δ ppm 7.61 (d, J=1.52 Hz, 1H) 7.55-7.58 (m,1H) 7.48-7.52 (m, 1H) 7.38-7.48 (m, 2H) 7.07-7.24 (m, 4H) 6.83-6.98 (m,2H) 5.74-5.97 (m, 1H) 4.72-4.80 (m, 1H) 4.52 (d, J=13.69 Hz, 1H) 4.29(d, J=11.15 Hz, 1H)

Example 13.(S)-6-benzhydryl-11-hydroxy-3-methyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Synthesized by the method of Example 7, except using 2-oxopropanalinstead of glyoxal. LCMS (m/z): 384.3 (MH⁺), 0.61 min, 1H NMR (400 MHz,CD3OD) δ ppm 7.40-7.47 (m, 5H) 7.35-7.40 (m, 1H) 7.16-7.30 (m, 6H) 6.04(d, J=7.19 Hz, 1H) 5.66 (dd, J=11.42, 2.96 Hz, 1H) 4.47 (dd, J=14.06,3.84 Hz, 1H) 4.26 (d, J=13.30 Hz, 1H) 4.07 (d, J=11.44 Hz, 1H) 2.02 (d,J=0.73 Hz, 3H)

Example 14.(S)-6-benzhydryl-11-hydroxy-2,3-dimethyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Synthesized by the method of Example 7, except using 2,3-butanedioneinstead of glyoxal. LCMS (m/z): 398.3 (MH⁺), 0.62 min, 1H NMR (400 MHz,CD₃OD) δ ppm 7.44 (d, J=4.35 Hz, 4H) 7.37 (dq, J=8.69, 4.20 Hz, 1H)7.16-7.30 (m, 6H) 6.03 (d, J=7.29 Hz, 1H) 5.64 (dd, J=11.40, 3.03 Hz,1H) 4.47 (dd, J=14.13, 3.86 Hz, 1H) 4.24 (d, J=13.74 Hz, 1H) 4.09 (d,J=11.44 Hz, 1H) 2.42 (s, 3H) 1.90-2.01 (m, 3H)

Example 15. (S)-6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4] pyrazino [1,2-b]pyridazin-10(6H)-one

Synthesized by the method of Example 1 except the enantiomers of thecorresponding intermediate 15.5 were separated by chiral HPLC. LCMS(m/z): 439.3 (MH⁺), 0.74 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.61 (dd,J=13.11, 1.52 Hz, 2H) 7.51 (s, 1H) 7.48 (s, 1H) 7.33-7.44 (m, 3H)7.14-7.24 (m, 3H) 7.07-7.12 (m, 1H) 5.89 (dd, J=11.05, 3.37 Hz, 1H) 4.78(dd, J=14.31, 4.33 Hz, 1H) 4.55 (d, J=13.94 Hz, 1H) 4.34 (d, J=11.10 Hz,1H)

Example 16.(R)-6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino [1,2-b]pyridazin-10(6H)-one

Synthesized by the method of Example 1 except the enantiomers of thecorresponding intermediate 16.5 were separated by chiral HPLC. LCMS(m/z): 439.3 (MH⁺), 0.73 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.62 (dd,J=12.74, 1.59 Hz, 2H) 7.51 (s, 1H) 7.48 (s, 1H) 7.33-7.44 (m, 3H)7.14-7.24 (m, 3H) 7.07-7.12 (m, 1H) 5.89 (dd, J=11.05, 3.37 Hz, 1H) 4.78(dd, J=14.38, 4.35 Hz, 1H) 4.56 (d, J=14.33 Hz, 1H) 4.35 (d, J=11.10 Hz,1H)

General Synthesis of Chiral Amino Alcohols

Step 1: ethyl (E)-3-(4-fluorophenyl)acrylate

Added a solution of n-butyllithium (2.5 M in hexane, 17.60 ml, 44.0mmol) dropwise to a solution of triethyl phosphonoacetate (8.01 ml, 40.0mmol) in THF (Volume: 40 ml) at −78° C. After 5 minutes,4-fluorobenzaldehyde (4.29 ml, 40 mmol) was added dropwise. The solutionwas then stirred for 10 minutes at −78° C. and RT for 2 hours. Thereaction was quenched with brine, diluted with diethyl ether and thenwashed 3 times with brine. The organic layer was dried (Na₂SO₄),filtered and concentrated to give crude ethyl(E)-3-(4-fluorophenyl)acrylate which was used without furtherpurification. MS m/z 195.1 (M+1).

Step 2: (E)-3-(4-fluorophenyl)prop-2-en-1-ol

Added a solution of DIBAL-H (1.0 M in toluene, 120 ml, 120 mmol) slowlyto a solution of crude ethyl (E)-3-(4-fluorophenyl)acrylate (7.77 g, 40mmol) in THF (Volume: 40 ml) at 0° C. After the addition was complete,the mixture was stirred at RT for 2 hours. The reaction was quenched bythe addition of saturated aqueous potassium-sodium tartrate (100 mL).The resulting solution was stirred at 40° C. and solid potassium-sodiumtartrate (˜30 grams) was added. The mixture was then cooled to RT anddiluted with diethyl ether (600 mL), washed with saturated aqueouspotassium-sodium tartrate (3×200 mL), dried (Na₂SO₄), filtered andconcentrated. Silica gel column chromatography (EtOAc/heptane) provided(E)-3-(4-fluorophenyl)prop-2-en-1-ol (4.12 g, white solid) in 68% yieldover 2 steps. ¹H NMR (400 MHz, Chloroform-d) δ 7.41-7.30 (m, 2H),7.05-6.95 (m, 2H), 6.59 (dt, J=15.8, 1.5 Hz, 1H), 6.28 (dt, J=15.9, 5.7Hz, 1H), 4.32 (dd, J=5.8, 1.6 Hz, 2H).

Step 3: ((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methanol

Added titanium isopropoxide (0.802 ml, 2.71 mmol) and tert-butylhydroperoxide (5.5 M in decane, 9.85 ml, 54.2 mmol) sequentially to astirred mixture of (+)-diisopropyl L-tartrate (0.708 ml, 3.38 mmol) and4 A molecular sieves (powdered) (1.3 g, 27.1 mmol) in DCM (Volume: 246ml) at −20° C. (under nitrogen). The mixture was stirred at −20° C. for1 hour, and then a solution of (E)-3-(4-fluorophenyl)prop-2-en-1-ol(4.12 g, 27.1 mmol) in DCM (7 mL) was added dropwise over 30 min. Themixture was stirred at −20° C. for 3 hours. The reaction was quenched at−20° C. with a 10% aqueous NaOH solution saturated with NaCl (2.7 mL).Then, diethyl ether (40 mL) was added and the cold bath was allowed towarm to 10° C. while MgSO₄ (2.7 grams) and celite (677 mg) were added.After another 15 minutes of stirring, the mixture was allowed to settleand then filtered through a pad of celite (washed with diethyl ether).The filtrate was concentrated. Silica gel column chromatography(EtOAc/heptane) provided ((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methanol(3.47 g, colorless oil) in 76% yield. ¹H NMR (400 MHz, Chloroform-d) δ7.30-7.21 (m, 2H), 7.09-7.00 (m, 2H), 4.04 (ddd, J=12.8, 5.2, 2.4 Hz,1H), 3.92 (d, J=2.2 Hz, 1H), 3.81 (ddd, J=12.7, 7.8, 3.7 Hz, 1H), 3.19(dt, J=4.2, 2.3 Hz, 1H), 1.87-1.77 (m, 1H).

Step 4:2-(((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methyl)isoindoline-1,3-dione

Added DEAD (1.22 ml, 7.73 mmol) dropwise to a solution of((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methanol (1 g, 5.95 mmol),phthalimide (0.962 g, 6.54 mmol), and triphenylphosphine (2.028 g, 7.73mmol) in THF (Volume: 19.8 ml) at RT. The yellow solution was stirredfor 30 minutes, by which time LCMS showed reaction complete. Thereaction mixture was concentrated. Silica gel column chromatography(EtOAc/heptane) provided2-(((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methyl)isoindoline-1,3-dione(1.6 g, white solid) in 91% yield. MS m/z 298.1 (M+1). ¹H NMR (400 MHz,Chloroform-d) δ 7.88 (dt, J=5.1, 2.5 Hz, 2H), 7.75 (ddd, J=8.6, 5.4, 3.1Hz, 2H), 7.25-7.18 (m, 2H), 7.07-6.95 (m, 2H), 4.14 (dd, J=14.3, 4.6 Hz,1H), 3.90-3.79 (m, 2H), 3.21 (ddd, J=5.6, 4.6, 2.0 Hz, 1H).

Step 5:2-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)isoindoline-1,3-dione

Added THF (Volume: 23.5 mL) to copper(I) bromide-dimethyl sulfidecomplex (484 mg, 2.35 mmol) and((2S,3S)-3-(4-fluorophenyl)oxiran-2-yl)methanol (700 mg, 2.35 mmol) atRT. Cooled to −20° C. in an acetone bath with periodic dry iceadditions. A solution of phenylmagnesium chloride (2.0 M in THF, 4.47mL, 8.95 mmol) was added dropwise. The reaction was quenched withsaturated aqueous NH₄Cl solution and extracted with diethyl ether (2times). The combined organic extracts were dried over MgSO₄, filteredand concentrated. Silica gel column chromatography (EtOAc/heptane)provided2-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)isoindoline-1,3-dione(0.463 g, white solid) in 52% yield. MS m/z 376.3 (M+1).

Step 6: (1R,2R)-3-amino-1-(4-fluorophenyl)-1-phenylpropan-2-ol

Added hydrazine (0.581 mL, 18.5 mmol) to a solution of2-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)isoindoline-1,3-dione(463 mg, 1.233 mmol) in ethanol (Volume: 10 mL) at RT. The mixture washeated at 65° C. for 1 hour, by which time LCMS showed reactioncomplete. The reaction was cooled to RT and concentrated on the rotovap.The residue was triturated with DCM and then filtered to remove solids.The filtrate was concentrated to give crude(1R,2R)-3-amino-1-(4-fluorophenyl)-1-phenylpropan-2-ol (254 mg, yellowfoam) in 84% yield that was used without further purification. MS m/z246.2 (M+1).

The intermediates in the following table were prepared by a methodsimilar to intermediate AA-1.

Interme- diate No. Structure Name Materials LCMS AA-2

(1S,2R)-3- amino-1-(4- fluorophenyl)-1- phenylpropan- 2-ol Step 1:benzaldehyde Step 5: 4- fluorophenylmagnesium bromide 246.2 AA-3

(1R,2R)-3- amino-1-(4- fluorophenyl)-1- (5-fluoropyridin-3-yl)propan-2-ol Step 1: 5- fluoronicotinaldehyde Step 5: 4-fluorophenylmagnesium bromide 265.2 AA-4

(1R,2R)-3- amino-1-(4- fluorophenyl)-1- (6- (trifluoromethyl) pyridin-3-yl)propan-2-ol Step 1: 6- (trifluoromethyl)nico- tinaldehyde Step 5: 4-fluorophenylmagnesium bromide 315.3 AA-5

(1S,2R)-3- amino-1-(4- fluorophenyl)-1- (3- (trifluoromethyl)phenyl)propan- 2-ol Step 1: 4- fluorobenzaldehyde Step 5: (3-(trifluoromethyl)phenyl) magnesium bromide 314.2 AA-6

(R)-3-amino- 1,1-bis(4- fluorophenyl) propan-2-ol Step 1: 4-fluorobenzaldehyde Step 5: 4- fluorophenylmagnesium bromide 264.2 AA-7

(R)-3-amino- 1,1-bis(3- fluorophenyl) propan-2-ol Step 1: 3-fluorobenzaldehyde Step 5: 3- fluorophenylmagnesium bromide 264.4 AA-8

(1S,2R)-3- amino-1-(3- fluorophenyl)-1- (4- fluorophenyl) propan-2-olStep 1: 4- fluorobenzaldehyde Step 5: 3- fluorophenylmagnesium bromide264.3 AA-9

(1S,2R)-3- amino-1-(3,4- difluorophenyl)- 1-(4- fluorophenyl)propan-2-ol Step 1: 4- fluorobenzaldehyde Step 5: 3,4- difluorophenyl-magnesium bromide 282.2 AA-10

(1R,2R)-3- amino-1-(3- fluorophenyl)-1- (4- fluorophenyl) propan-2-olStep 1: 3- fluorobenzaldehyde Step 5: 4- fluorophenylmagnesium bromide264.2 AA-11

(1S,2R)-3- amino-1-(4- fluoro-2- methylphenyl)- 1-(4- fluorophenyl)propan-2-ol Step 1: 4- fluorobenzaldehyde Step 5: (4-fluoro-2-methylphenyl) magnesium bromide 278.2 AA-12

(1S,2R)-3- amino-1-(4- fluorophenyl)-1- (3- (methylthio) phenyl)propan-2-ol Step 1: 4- fluorobenzaldehyde Step 5: (3- (methylthio)phenyl)magnesium bromide 292.2 AA-13

(1S,2R)-3- amino-1-(2- chlorophenyl)-1- (4- fluorophenyl) propan-2-olStep 1: 4- fluorobenzaldehyde Step 5: (2- chlorophenyl) magnesiumbromide 280.2 AA-14

(1S,2R)-3- amino-1-(3- bromophenyl)- 1-(4- fluorophenyl) propan-2-olStep 1: 4- fluorobenzaldehyde Step 5: (3- bromophenyl) magnesium bromide324.1 AA-15

(1S,2R)-3- amino-1-(3- chlorophenyl)-1- (4- fluorophenyl) propan-2-olStep 1: 4- fluorobenzaldehyde Step 5: (3- chlorophenyl) magnesiumbromide 280.1 AA-16

(1R,2R)-3- amino-1-(4- fluorophenyl)-1- (4- (trifluoromethyl)phenyl)propan- 2-ol Step 1: 4- fluorobenzaldehyde Step 5: (4-trifluoromethylphenyl) magnesium bromide 314.2 AA-17

(1S,2R)-3- amino-1-(4- chlorophenyl)-1- (4- fluorophenyl) propan-2-olStep 1: 4- fluorobenzaldehyde Step 5: (4- chlorophenyl) magnesiumbromide 280.1 AA-18

(1S,2R)-3- amino-1-(3,5- difluorophenyl)- 1-(4- fluorophenyl)propan-2-ol Step 1: 4- fluorobenzaldehyde Step 5: (3,5- difluorophenyl)magnesium bromide 282.1 AA-19

(1R,2R)-3- amino-1-(2- bromo-4- fluorophenyl)-1- (o-tolyl)propan- 2-olStep 1: 2-bromo-4- fluorobenzaldehyde Step 5: (2- methylphenyl)magnesium bromide 338.2 AA-20

(1R,2R)-3- amino-1-(2- bromo-4- fluorophenyl)-1- (3- fluorophenyl)propan-2-ol Step 1: 2-bromo-4- fluorobenzaldehyde Step 5: (3-fluorophenyl) magnesium bromide 342.2 AA-21

(1R,2R)-3- amino-1-(3- bromo-4- fluorophenyl)-1- phenylpropan- 2-ol Step1: 3-bromo-4- fluorobenzaldehyde Step 5: phenylmagnesium chloride 324.1AA-22

(1S,2R)-3- amino-1-(4- fluorophenyl)-1- (m-tolyl)propan- 2-ol Step 1: 4-fluorobenzaldehyde Step 5: (3- methylphenyl) magnesium bromide 260.2AA-23

(1R,2R)-3- amino-1-(2- bromo-4- fluorophenyl)-1- (4- fluorophenyl)propan-2-ol Step 1: 2-bromo-4- fluorobenzaldehyde Step 5: (4-fluorophenyl) magnesium bromide 342.1 AA-24

(1S,2R)-3- amino-1-(4- fluorophenyl)-1- (o-tolyl)propan- 2-ol Step 1: 4-fluorobenzaldehyde Step 5: (2- methylphenyl) magnesium bromide 260.2AA-25

(1R,2R)-3- amino-1-(4- fluorophenyl)-1- (p-tolyl)propan- 2-ol Step 1: 4-fluorobenzaldehyde Step 5: (4- methylphenyl) magnesium bromide 260.2

Synthesis of intermediate AA-26(1S,2R)-3-amino-1-(4-fluorophenyl)-1-(3-(methylsulfonyl)phenyl)propan-2-ol

Step 1: 2-((2R,3S)-3-(4-fluorophenyl)-2-hydroxy-3-(3-(methylsulfonyl)phenyl) propyl) isoindoline-1,3-dione

Added a solution of OXONE (175 mg, 0.285 mmol) in water (Volume: 3.00 mLto2-((2R,3S)-3-(4-fluorophenyl)-2-hydroxy-3-(3-(methylthio)phenyl)propyl)isoindoline-1,3-dione(60 mg, 0.142 mmol, Synthesis: see intermediate AA-12, steps 1-5) in THF(Volume: 3 mL) at 0° C. Reaction mixture was stirred in ice bath for 3H.LC-MS at this point showed major desired product. The reaction wasquenched with saturated sodium thiosulfate solution and was extractedwith EtOAc (twice). The combined organic extracts were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to providecrude 2-((2R,3S)-3-(4-fluorophenyl)-2-hydroxy-3-(3-(methylsulfonyl)phenyl) propyl)isoindoline-1,3-dione (65.0 mg, 0.142 mmol, 100% yield).LCMS: MH⁺454.3, 0.91 min.

Proceed for next step without further purification.

Step 2:(1S,2R)-3-amino-1-(4-fluorophenyl)-1-(3-(methylsulfonyl)phenyl)propan-2-ol

Prepared from2-((2R,3S)-3-(4-fluorophenyl)-2-hydroxy-3-(3-(methylsulfonyl) phenyl)propyl)isoindoline-1,3-dione by the method of intermediate AA-1, step 6.LCMS: MH⁺ 324.3, 0.67 min.

Synthesis of Intermediate AA-27

Step 1:4-((1R,2R)-3-(1,3-dioxoisoindolin-2-yl)-1-(4-fluorophenyl)-2-hydroxypropyl)benzonitrile

Added2-((2R,3S)-3-(4-chlorophenyl)-3-(4-fluorophenyl)-2-hydroxpropyl)isoindoline-1,3-dione(250 mg, 0.610 mmol, Synthesis: see intermediate AA-17, steps 1-5), zincpowder (39.9 mg, 0.610 mmol), zinc cyanide (143 mg, 1.22 mmol),rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (48.6 mg, 0.122 mmol) andbis(2,2,2-trifluoroacetyl)palladium (18 mg, 0.061 mmol) at RT to amicrowave vial equipped with a stir bar. Cap was sealed and N2 waspassed through for 5 min. Then added DMA (Volume: 5 mL) through thesyringe and N2 was passed through for an additional 5 min. The microwavevial was placed in a heating block and heated at 95° C. for 1 hour.LC-MS showed complete reaction. Reaction mixture was diluted with DCMand filtered through celite. Washed with DCM and solvent was evaporated.The crude material was purified by silica gel chromatography using 0-40%EtOAc/heptane to give4-((1R,2R)-3-(1,3-dioxoisoindolin-2-yl)-1-(4-fluorophenyl)-2-hydroxypropyl)benzonitrile,(195 mg, 0.463 mmol, 76% yield). LCMS: MH+401.3, 0.79 min. 1H NMR (400MHz, CDCl3) δ ppm 7.79-7.86 (m, 2H) 7.68-7.76 (m, 2H) 7.55-7.61 (m, 2H)7.45-7.51 (m, 2H) 7.29-7.36 (m, 2H) 7.01 (t, J=8.58 Hz, 2H) 4.62-4.79(m, 1H) 4.05-4.14 (m, 1H) 3.68-3.87 (m, 2H) 2.46 (d, J=5.23 Hz, 1H).

Step 2:4-((1R,2R)-3-amino-1-(4-fluorophenyl)-2-hydroxypropyl)benzonitrile

Prepared from4-((1R,2R)-3-(1,3-dioxoisoindolin-2-yl)-1-(4-fluorophenyl)-2-hydroxypropyl)benzonitrileby the method of intermediate AA-1, step 6. LCMS: MH+ 271.3, 0.63 min.

The intermediates in the following table were prepared by a methodsimilar to intermediate AA-27.

Interme- diate No. Structure Name Starting Material LCMS AA-28

3-((1S,2R)-3- amino-1-(4- fluorophenyl)-2- hydroxypropyl) benzonitrileStep 1: 2-((2R,3S)-3- (3-chlorophenyl)-3-(4- fluorophenyl)-2-hydroxypropyl) isoindoline-1,3-dione 271.1 AA-29

2-((1S,2R)-3- amino-1-(4- fluorophenyl)-2- hydroxypropyl) benzonitrileStep 1: 2-((2R,3S)-3- (2-chlorophenyl)-3-(4- fluorophenyl)-2-hydroxypropyl) isoindoline-1,3-dione 271.2 AA-30

3-((1R,2R)-3- amino-1-(3- fluorophenyl)-2- hydroxypropyl) benzonitrileStep 1: 2-((2R,3S)-3- (3-chlorophenyl)-3-(3- fluorophenyl)-2-hydroxypropyl) isoindoline-1,3-dione 271.2

Example 17.(S)-6-((R)-(4-fluorophenyl)(phenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

Step 1:5-(benzyloxy)-3-(1-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one

Ammonium acetate (118 mg, 1.53 mmol) and glyoxal (40% in water, 0.18 mL,1.53 mmol) were added to a solution of5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carbaldehyde (551 mg, 1.53 mmol) and(1R,2R)-3-amino-1-(4-fluorophenyl)-1-phenylpropan-2-ol (250 mg, 1.02mmol) in MeOH (5 mL). The mixture was heated at reflux for 2 hours andthen cooled to room temperature. The reaction was diluted with EtOAc andwashed with dilute brine. The organic layer was dried (Na₂SO₄), filteredand concentrated. Silica gel column chromatography (EtOAc/heptane/MeOH)provided5-(benzyloxy)-3-(1-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(0.143 g, yellow oil) in 22% yield. MS m/z 627.4 (M+1).

Step 2:(1R,2R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-(4-fluorophenyl)-1-phenylpropan-2-ylmethanesulfonate

Methanesulfonyl chloride (0.036 mL, 0.46 mmol) was added dropwise to asolution of5-(benzyloxy)-3-(1-((2R,3R)-3-(4-fluorophenyl)-2-hydroxy-3-phenylpropyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(1H)-one(143 mg, 0.228 mmol) and Et₃N (0.095 mL, 0.68 mmol) in DCM (4.5 mL) at0° C. The mixture was stirred at the same temperature for 30 min andthen quenched with water. The layers were separated and the aqueouslayer was extracted with DCM. The combined organic extracts were washedwith brine, filtered and concentrated. Silica gel column chromatography(EtOAc/Heptane/MeOH) provided(1R,2R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-(4-fluorophenyl)-1-phenylpropan-2-ylmethanesulfonate (100 mg, yellow oil) in 62% yield. MS m/z 705.3 (M+1).

Step 3:(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate

10% Pd/C (15 mg) was added to a solution of(1R,2R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-(4-fluorophenyl)-1-phenylpropan-2-ylmethanesulfonate (100 mg, 0.142 mmol) in MeOH (10 mL) under nitrogen atroom temperature. The flask was then evacuated and refilled with H₂ froma balloon (three times) and then stirred vigorously under a balloonatmosphere of H₂ for 30 min. The reaction flask was then purged withnitrogen and the mixture was filtered through celite. The filtrate wasconcentrated to give crude(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z615.3 (M+1).

Step 4:(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate

Crude(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate was dissolved in TFA (5 mL) and stirred at roomtemperature for 2 hours. The reaction was then concentrated. The residuewas taken up in toluene and concentrated again to give crude(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate, which was used without further purification. MS m/z485.2 (M+1).

Step 5:(S)-6-((R)-(4-fluorophenyl)(phenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

K₂CO₃ (59 mg, 0.43 mmol) was added to a solution of crude(1R,2R)-1-(4-fluorophenyl)-3-(2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1-phenylpropan-2-ylmethanesulfonate in DMF (2 mL). The mixture was stirred at roomtemperature for 3 hours and then filtered to remove solids. The filtratewas purified by reverse phase HPLC. Product fractions were combined,frozen and lyophilized to afford a TFA salt of6-benzhydryl-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one(26 mg, 0.051 mmol, white solid) in 36% yield over three steps. ¹H NMR(400 MHz, DMSO-d₆) δ 7.67 (d, J=1.6 Hz, 1H), 7.56 (s, 1H), 7.54-7.46 (m,2H), 7.35 (s, 1H), 7.25-7.08 (m, 7H), 5.88 (dd, J=11.2, 4.0 Hz, 1H),4.71 (dd, J=14.1, 4.2 Hz, 1H), 4.36 (d, J=14.2 Hz, 1H), 4.28 (d, J=11.4Hz, 1H). MS m/z 389.3 (M+1).

The compounds in the following table were prepared by a method similarto Example 17. In some cases steps 3 & 4 were replaced with microwaveheating in neat TFA at 80-100° C. for 30-60 min.

Example Starting Mass No. Material Structure M + H 1H NMR 18 AA-2

389.3 (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 1.6Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.42 (s, 1H), 7.38 (t, J = 7.5 Hz,2H), 7.33-7.20 (m, 3H), 6.99 (t, J = 8.8 Hz, 2H), 5.93-5.84 (m, 1H),4.73 (dd, J = 14.1, 4.3 Hz, 1H), 4.32 (dd, J = 12.8, 10.0 Hz, 2H). 19AA-3

408.3 (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.7 Hz, 1H), 8.50 (t, J = 1.7Hz, 1H), 8.07 (dt, J = 10.1, 2.3 Hz, 1H), 7.72-7.60 (m, 2H), 7.47-7.41(m, 1H), 7.33-7.24 (m, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.96 (dd, J =11.3, 3.9 Hz, 1H), 4.75 (dd, J = 14.3, 4.1 Hz, 1H), 4.60-4.53 (m, 1H),4.46 (d, J = 14.2 Hz, 1H). 20 AA-4

458.4 (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.30 (dd, J = 7.9, 2.2 Hz, 1H),7.95 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.37(s, 1H), 7.33-7.22 (m, 2H), 7.04 (t, J = 8.8 Hz, 2H), 6.05-5.95 (m, 1H),4.73 (dd, J = 14.3, 3.9 Hz, 1H), 4.62-4.54 (m, 1H), 4.41 (d, J = 14.2Hz, 1H). 21 AA-5

457.3 (400 MHz, MeOD) δ ppm 4.49 (d, J = 11.30 Hz, 1 H) 4.57 (d, J =14.33 Hz, 1 H) 4.80 (dd, J = 14.33, 4.25 Hz, 1 H) 5.91 (dd, J = 11.25,3.91 Hz, 1 H) 7.17 (t, J = 8.66 Hz, 2 H) 7.36- 7.42 (m, 1 H) 7.44 (s, 1H) 7.46- 7.58 (m, 5 H) 7.64 (d, J = 1.37 Hz, 1 H) 7.68 (s, 1 H) 22 AA-6

407.3 (400 MHz, MeOD) δppm 7.40 (s, 4 H) 7.35 (s, 1 H) 7.07-7.23 (m, 4H) 6.88 (t, J = 8.68 Hz, 2 H) 5.70 (br d, J = 11.30 Hz, 1 H) 4.67 (brdd,J = 13.99, 3.96 Hz, 1 H) 4.38 (br d, J = 13.99 Hz, 1 H) 4.16 (br d, J =11.35 Hz, 1 H) 23 AA-7

407.3 (400 MHz, MeOD) δ ppm 7.52- 7.63 (m, 2 H) 7.40-7.51 (m, 2 H)7.15-7.28 (m, 3 H) 6.99-7.11 (m, 2 H) 6.87-6.97 (m, 2 H) 5.86 (dd, J =11.20, 3.52 Hz, 1 H) 4.76 (dd, J = 14.28, 4.21 Hz, 1 H) 4.52 (d, J =14.18 Hz, 1 H) 4.34 (d, J = 11.25 Hz, 1 H) 24 AA-8

407.3 (400 MHz, MeOD)δ ppm 4.36 (d, J = 11.20 Hz, 1 H) 4.55 (d, J =14.33 Hz, 1 H) 4.78 (dd, J = 14.33, 4.35 Hz, 1 H) 5.86(dd, J = 11.10,3.86 Hz, 1 H) 6.85-6.97 (m, 2 H) 7.01 (br d, J = 10.17 Hz, 1 H)7.08-7.22 (m, 3 H) 7.45 (dd, J = 8.61, 5.23 Hz, 2 H) 7.52 (s, 1 H)7.62(d, J = 1.32 Hz, 1 H) 7.66 (d, J = 1.37 Hz, 1 H) 25 AA-9

425.3 (400 MHz, MeOD)δ ppm 4.35 (d, J = 11.35 Hz, 1 H) 4.53 (d, J =14.33 Hz, 1 H) 4.77 (dd, J = 14.33, 4.30 Hz, 1 H) 5.84 (dd, J = 11.30,3.81 Hz, 1 H) 6.93-6.99 (m, 1 H) 7.07 (dt, J = 10.27, 8.44 Hz, 1 H)7.12-7.28 (m, 3 H) 7.45 (dd, J = 8.61, 5.23 Hz, 2 H) 7.57 (s, 1 H) 7.62(s, 1 H) 7.67(s, 1 H) 26 AA-10

407.3 (400 MHz, MeOD) δ ppm 4.34 (d, J = 11.25 Hz, 1 H) 4.51-4.61 (m, 1H) 4.79 (dd, J = 14.31, 4.28 Hz, 1 H) 5.86 (dd, J = 11.20, 3.81 Hz, 1H)6.92 (t, J = 8.71 Hz, 2 H) 7.02-7.12 (m, 1 H) 7.14-7.30 (m, 4 H) 7.36-7.46 (m, 1 H) 7.47-7.54 (m, 1 H) 7.64 (dd, J = 12.28, 1.47 Hz, 2 H) 27AA-11

421.3 (400 MHz, MeOD) δ ppm 1.90- 2.12 (m, 3 H) 4.46 (d, J = 10.71 Hz, 1H) 4.55 (d, J = 13.55 Hz, 1 H) 4.77 (dd, J = 14.26, 4.23 Hz, 1 H)5.90(dd, J = 10.64, 3.01 Hz, 1 H) 6.74 (dd, J = 9.81, 2.67 Hz, 1 H)6.86-6.98 (m, 1 H) 6.86-6.98 (m, 1 H) 7.11 (t, J = 8.68 Hz, 2 H) 7.37(dd, J = 8.66, 5.18 Hz, 2 H) 7.57 (s, 2 H) 7.59 (s, 1 H) 7.63 (dd, J =8.73, 5.70 Hz, 1 H) 28 AA-12

435.3 (400 MHz, MeOD) δ ppm 2.27- 2.42 (m, 3 H) 4.29 (d, J = 10.96 Hz, 1H) 4.56 (d, J = 14.23 Hz, 1 H) 4.78 (dd, J = 14.26, 4.28 Hz, 1 H) 5.82(dd, J = 10.91, 3.81 Hz, 1 H) 6.84- 7.01 (m, 2 H) 7.02-7.22 (m, 4 H)7.46 (dd, J = 8.61, 5.23 Hz, 2 H) 7.50 (s, 1 H) 7.62 (d, J = 10.71 Hz, 2H) 29 AA-13

423.3 (400 MHz, MeOD) δ ppm 4.58 (d, J = 14.13 Hz, 1 H) 4.81 (dd, J =14.23, 4.06 Hz, 1 H) 4.90 (br s, 1 H) 4.95-4.95 (m, 1 H) 5.91 (dd, J =11.44, 3.23 Hz, 1 H) 7.10-7.23 (m, 4 H) 7.23-7.33 (m, 1 H) 7.40- 7.52(m, 3 H) 7.61 (d, J = 8.85 Hz, 2 H) 7.68 (d, J = 7.78 Hz, 1 H) 30 AA-14

467.2 (400 MHz, MeOD) δ ppm 7.65 (d, J = 1.42 Hz, 1 H) 7.61 (d, J = 1.42Hz, 1 H) 7.53 (s, 1 H) 7.45 (dd, J = 8.66, 5.23 Hz, 2 H) 7.30-7.36 (m, 2H) 7.07-7.19 (m, 4 H) 5.84 (dd, J = 11.00, 3.67 Hz, 1 H) 4.78 (dd, J =14.33, 4.35 Hz, 1 H) 4.55 (d, J = 14.33 Hz, 1 H) 4.34 (d, J = 11.10 Hz,1 H) 31 AA-15

423.1 (400 MHz, MeOD) δ ppm 7.63 (d, J = 1.47 Hz, 1 H) 7.59 (d, J = 1.42Hz, 1 H) 7.52 (s, 1 H) 7.45 (dd, J = 8.63, 5.21 Hz, 2 H) 7.21 (s, 1H)7.12- 7.20 (m, 4 H) 7.06-7.11 (m, 1 H) 5.84 (dd, J = 11.10, 3.67 Hz, 1H) 4.77 (dd, J = 14.28, 4.30 Hz, 1 H) 4.54 (d, J = 14.33 Hz, 1 H) 4.33(d, J = 11.10 Hz, 1 H) 32 AA-16

457.3 (400 MHz, MeOD) δ ppm 4.46 (d, J = 11.25 Hz, 1 H) 4.57 (d, J =14.28 Hz, 1 H) 4.80 (dd, J = 14.31, 4.33 Hz, 1 H) 5.92 (dd, J = 11.18,3.79 Hz, 1 H) 7.15 (t, J = 8.68 Hz, 2 H) 7.37- 7.53 (m, 6 H) 7.63 (s, 1H) 7.67 (d, J = 1.17 Hz, 1 H) 33 AA-17

423.3 (400 MHz, MeOD) δ ppm 7.63 (d, J = 1.42 Hz, 1 H) 7.61-7.66 (m, 1H) 7.59 (d, J = 1.42 Hz, 1 H) 7.53 (s, 1 H) 7.43 (dd, J = 8.66, 5.23 Hz,2 H) 7.10-7.22 (m, 6 H) 5.83 (dd, J = 11.18, 3.69 Hz, 1 H) 4.77 (dd, J =14.31, 4.33 Hz, 1 H) 4.53 (d, J = 14.23 Hz, 1 H) 4.31 (d, J = 11.20 Hz,1 H) 34 AA-18

425.3 (400 MHz, MeOD) δ ppm 4.34 (br d, J = 14.18 Hz, 1 H) 4.48 (br d, J= 11.59 Hz, 1 H) 4.71 (br dd, J = 14.23, 4.16 Hz, 1 H) 5.94 (dd, J =11.62, 3.64 Hz, 1 H) 6.96- 7.13 (m, 3 H) 7.22 (t, J = 8.78 Hz, 2 H)7.41-7.58 (m, 3 H) 7.65 (d, J = 1.13 Hz, 1 H) 7.70 (d, J = 1.17 Hz, 1 H)35 AA-19

481.2 (500 MHz, CD3OD) δ 7.11 (dd, J = 9.0, 5.8 Hz, 1H), 6.83-6.73 (m,4H), 6.64 (dd, J = 8.3, 2.6 Hz, 1H), 6.53-6.45 (m, 1H), 6.41 (t, J = 7.8Hz, 1H), 6.35-6.30 (m, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.09 (d, J = 9.7Hz, 1H), 4.27 (d, J = 9.7 Hz, 1H), 4.04-4.01 (m, 1H), 3.96-3.86 (m, 1H),1.24 (s, 3H). 36 AA-20

487.2 (500 MHz, CD3OD) δ 7.21 (dd, J = 8.8, 5.7 Hz, 1H), 6.88-6.83 (m,2H), 6.73-6.66 (m, 2H), 6.57 (td, J = 8.3, 2.6 Hz, 1H), 6.45-6.38 (m,1H), 6.26-6.20 (m, 1H), 6.15 (t, J = 8.8 Hz, 2H), 5.12 (dd, J = 11.2,3.8 Hz, 1H), 4.01 (dd, J = 14.5, 4.1 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H),3.74 (d, J = 14.4 Hz, 1H). 37 AA-21

469.2 (500 MHz, CD3OD) δ 6.94 (d, J = 6.4 Hz, 1H), 6.89-6.84 (m, 2H),6.69 (d, J = 2.0 Hz, 2H), 6.46 (t, J = 8.5 Hz, 1H), 6.40 (dd, J = 5.5,1.7 Hz, 3H), 6.35 (d, J = 6.1 Hz, 2H), 5.09 (d, J = 9.7 Hz, 1H), 4.03-3.98 (m, 1H), 3.83 (d, J = 14.3 Hz, 1H), 3.56 (d, J = 11.0 Hz, 1H). 38AA-22

403.3 (500 MHz, CD3OD) δ 6.80 (t, J = 10.1 Hz, 3H), 6.74 (d, J = 2.1 Hz,1H), 6.62-6.55 (m, 2H), 6.39 (t, J = 7.5 Hz, 1H), 6.34-6.26 (m, 3H),6.19 (d, J = 7.5 Hz, 1H), 5.13 (d, J = 10.9 Hz, 1H), 4.00 (d, J = 15.3Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.72 (d, J = 10.4 Hz, 1H), 1.19 (s,3H). 39 AA-23

487.0 (500 MHz, CD3OD) δ 7.27-7.17 (m, 1H), 6.89-6.84 (m, 2H), 6.71 (d,J = 2.6 Hz, 1H), 6.67 (dt, J = 8.4, 2.7 Hz, 1H), 6.56 (td, J = 8.3, 2.8Hz, 1H), 6.40 (ddd, J = 8.2, 5.1, 2.5 Hz, 2H), 6.14 (td, J = 9.0, 2.5Hz, 2H), 5.10 (dd, J = 11.4, 3.7 Hz, 1H), 4.04-3.98 (m, 1H), 3.93 (dd, J= 11.4, 2.4 Hz, 1H), 3.75 (d, J = 14.2 Hz, 1H). 40 AA-24

403.4 (500 MHz, CD3OD) δ 6.80 (t, J = 10.1 Hz, 3H), 6.74 (d, J = 2.1 Hz,1H), 6.59 (dd, J = 8.5, 5.2 Hz, 2H), 6.39 (t, J = 7.5 Hz, 1H), 6.30 (dt,J = 18.7, 7.9 Hz, 3H), 6.19 (d, J = 7.9 Hz, 1H), 5.13 (d, J = 10.9 Hz,1H), 4.00 (d, J = 13.0 Hz, 1H), 3.80 (d, J = 14.5 Hz, 1H), 3.72 (d, J =10.5 Hz, 1H), 1.19 (s, 3H). 41 AA-25

403.3 (500 MHz, CD3OD) δ 6.84 (d, J = 1.6 Hz, 1H), 6.81 (t, J = 1.7 Hz,1H), 6.71 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 8.6, 5.3 Hz, 2H), 6.36-6.31 (m, 2H), 6.25-6.18 (m, 4H), 5.07-4.98 (m, 1H), 3.98 (dd, J = 14.4,4.3 Hz, 1H), 3.77 (d, J = 14.1 Hz, 1H), 3.45 (d, J = 10.9 Hz, 1H), 1.45(d, J = 2.5 Hz, 3H). 42 AA-26

467.1 (400 MHz, MeOD) δ ppm 3.03 (s, 3 H) 4.48-4.60 (m, 2 H) 4.79 (brdd, J = 14.23, 4.21 Hz, 1 H) 5.92 (dd, J = 11.30, 3.86 Hz, 1 H) 7.18 (t,J = 8.66 Hz, 2 H) 7.42-7.55 (m, 4 H) 7.56-7.63 (m, 2 H) 7.65 (s, 1 H)7.71-7.82 (m, 2 H) 43 AA-28

414.3 (400 MHz, MeOD) δ ppm 4.45 (d, J = 11.40 Hz, 1 H) 4.56 (d, J =14.43 Hz, 1 H) 4.79 (dd, J = 14.33, 4.30 Hz, 1 H) 5.93 (dd, J = 11.32,3.74 Hz, 1 H) 7.17 (t, J = 8.66 Hz, 2 H) 7.34- 7.42 (m, 1 H) 7.43-7.52(m, 3 H) 7.52-7.58 (m, 2 H) 7.63-7.68 (m, 2 H) 7.68-7.71 (m, 1 H) 44AA-29

414.3 (400 MHz, MeOD) δ ppm 4.57- 4.71 (m, 2 H) 4.76-4.84 (m, 1 H) 5.98(br dd, J = 11.66, 3.01 Hz, 1 H) 7.12-7.26 (m, 3 H) 7.34-7.40(m, 1 H)7.41 (s, 1 H) 7.47-7.56 (m, 3 H) 7.59-7.68 (m, 3 H) 7.84 (d, J = 8.12Hz, 1 H) 45 AA-27

414.3 (400 MHz, MeOD) δ ppm 7.67 (d, J = 1.56 Hz, 1 H) 7.62 (d, J = 1.47Hz, 1 H) 7.56 (d, J = 8.31 Hz, 2 H) 7.51 (s, 1 H) 7.40-7.49 (m, 4 H)7.12- 7.21 (m, 2 H) 5.92 (dd, J = 11.20, 3.62 Hz, 1 H) 4.79 (dd, J =14.35, 4.33 Hz, 1 H) 4.55 (d, J = 14.38 Hz, 1 H) 4.46 (d, J = 11.35 Hz,1 H) 46 AA-30

414.3 (400 MHz, MeOD)δ ppm 4.47 (d, J = 11.44 Hz, 1 H) 4.57 (d, J =14.28 Hz, 1 H) 4.81 (dd, J = 14.38, 4.25 Hz, 1 H) 5.91-6.02 (m, 1 H)7.06- 7.20 (m, 1 H) 7.24-7.32 (m, 2 H) 7.34-7.52 (m, 3 H) 7.57 (d, J =8.02 Hz, 2 H) 7.60-7.73 (m, 3 H)

Example 47.(S)-6-(bis(4-fluorophenyl)methyl)-2,3-dibromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

Step 1:(R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-5-bromo-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate

Added NBS (140 mg, 0.789 mmol) to a solution of(R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate (500 mg, 0.657 mmol, prepared by the method of Example17, steps 1-2) in DCM (Volume: 12 mL). The reaction mixture was heatedat 60° C. for 1 hour. LC-MS showed complete reaction with major desiredmono bromo product and minor di bromo product. The reaction was quenchedwith water and the layers were separated. The aqueous layer wasextracted with DCM and the combined organic layers were washed withbrine, dried over Na2SO4, filtered and concentrated. The crude waspurified by silica gel chromatography using 0-100% EtOAc (containing 10%MeOH)/Heptane to give(R)-3-(2-(5-(benzyloxy)-4-oxo-1((2-(trimethylsilyl) ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-5-bromo-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate as a yellow solid, (350 mg, 0.437 mmol, 66.4% yield).LCMS: MH+801.4, 1.17 min.

Step 2:(R)-3-(5-bromo-2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate

Added TFA (1 mL, 13 mmol) to(R)-3-(2-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl) ethoxy)methyl)-1,4-dihydropyridazin-3-yl)-5-bromo-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate (55 mg, 0.069 mmol). Heated in microwave at 80° C. for60 min. LC-MS showed complete reaction. Solvent was evaporated andazeotroped with toluene. LCMS: MH+581.2, 0.80 min. Proceed to next stepwithout further purification.

Step 3:(S)-6-(bis(4-fluorophenyl)methyl)-3-bromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

To(R)-3-(5-bromo-2-(5-hydroxy-4-oxo-1,4-dihydropyridazin-3-yl)-1H-imidazol-1-yl)-1,1-bis(4-fluorophenyl)propan-2-ylmethanesulfonate (14.0 mg, 0.024 mmol) in DMF (Volume: 1 mL) was addedpotassium carbonate (11.6 mg, 0.0.084 mmol) at RT. Reaction mixture wasstirred at RT overnight. LC-MS showed complete reaction. The reactionmixture was filtered and the crude solution was purified by prep HPLC toobtain(S)-6-(bis(4-fluorophenyl)methyl)-3-bromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-oneas a TFA salt, (4.2 mg, 6.87 μmol, 28.3% yield). LCMS (m/z): 485.3(MH+), 0.85 min, 1H NMR (400 MHz, CD₃OD) δ ppm 4.19 (d, J=11.35 Hz, 1H)4.27 (d, J=13.89 Hz, 1H) 4.54 (dd, J=13.96, 4.08 Hz, 1H) 5.81 (dd,J=11.27, 3.50 Hz, 1H) 6.89-6.97 (m, 2H) 7.15 (t, J=8.68 Hz, 2H) 7.23(dd, J=8.61, 5.23 Hz, 2H) 7.44 (dd, J=8.58, 5.26 Hz, 2H) 7.50 (s, 1H)7.53 (s, 1H).

Example 48.(S)-6-(bis(4-fluorophenyl)methyl)-2,3-dibromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

Prepared by the method of Example 47.

LCMS (m/z): 563.3 (MH+), 0.97 min, 1H NMR (400 MHz, CD3OD) δ ppm4.13-4.30 (m, 2H) 4.50-4.64 (m, 1H) 5.76 (br dd, J=11.18, 2.91 Hz, 1H)6.91 (t, J=8.63 Hz, 2H) 7.14 (t, J=8.66 Hz, 2H) 7.22 (dd, J=8.49, 5.31Hz, 2H) 7.38-7.53 (m, 3H).

Example 49.(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrile

Step 1:(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-bromo-5H-imidazopyrazino[1,2-b]pyridazin-10(6H)-one

To crude(S)-6-(bis(4-fluorophenyl)methyl)-3-bromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one (Example 47, 209 mg, 0.431mmol) in DMF (Volume: 5 mL) was added potassium carbonate (208 mg, 1.507mmol) and benzyl bromide (0.128 mL, 1.077 mmol) at RT. Reaction mixturewas stirred at RT overnight. LC-MS showed complete reaction. Thereaction mixture was partitioned between EtOAc/water. The EtOAc layerwas separated and washed with brine. Dried over sodium sulfate, filteredand evaporated. The crude was purified by silica gel chromatographyusing 0-100% EtOAc (contains 10% MeOH)/Heptane to give(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-bromo-5H-imidazo[2′,1′:3,4] pyrazino[1,2-b]pyridazin-10(6H)-one, (190 mg, 0.297 mmol,69% yield). LCMS: MH+575.2, 1.12 min.

Step 2:(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrile

To (S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-bromo-5H-imidazo[2′,1′:3,4] pyrazino[1,2-b]pyridazin-10(6H)-one (20 mg, 0.035 mmol) inDMF (Volume: 1 mL) was added Zn(CN)2 (12.24 mg, 0.104 mmol) andPd(Ph3P)4 (6.02 mg, 5.21 μmol). Purged with N2 and reaction mixture washeated in microwave at 100° C. for 60 min. LC-MS showed major desiredproduct and minor SM. Reaction was stopped. The reaction mixture waspartitioned between EtOAc/water. The EtOAc layer was separated andwashed with brine. Dried over sodium sulfate, filtered and evaporated.The crude(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrilewas used in the next step. LCMS: MH+522.2, 1.06 min.

Step 3:(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrile

To crude(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrilewas added TFA (1 mL). Reaction mixture was heated at 90° C./20 min inmicrowave. LC-MS showed complete reaction. The solvent was evaporatedand azeotroped with toluene. The crude was dissolved in DMSO andpurified through prep-HPLC using ACN/Water/0.1% TFA to obtain(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbonitrile as a TFA salt, (3.5mg, 6.22 μmol, 18% yield). LCMS (m/z): 432.2 (MH+), 0.92 min, 1H NMR(400 MHz, CD3OD) δ ppm 4.16 (br d, J=11.25 Hz, 1H) 4.27 (br d, J=13.94Hz, 1H) 4.72 (br dd, J=14.06, 3.69 Hz, 1H) 5.81 (br dd, J=11.27, 3.20Hz, 1H) 6.92 (br t, J=8.68 Hz, 2H) 7.13-7.27 (m, 4H) 7.37-7.55 (m, 3H)8.08 (s, 1H).

Example 50:(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

Step 1:(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-vinyl-5H-imidazopyrazino[1,2-b]pyridazin-10(6H)-one

To (S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-bromo-5H-imidazo[2′,1′:3,4] pyrazino[1,2-b]pyridazin-10(6H)-one (For synthesis seeExample 49 Step 1, 90 mg, 0.156 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (48.2 mg, 0.312 mmol) inDME (Volume: 2 mL) and aqueous sodium carbonate (1 M, 400 μL, 0.400mmol) was added PdCl2(dppf). CH2C12 adduct (12.8 mg, 0.0156 mmol).Reaction mixture was heated in microwave at 110° C. for 15 min. LC-MSshowed complete reaction. Reaction mixture was partitioned between EtOAcand water. The organic layer was separated, dried over sodium sulfate,filtered and concentrated. The crude was purified by silica gelchromatography using 0-100% EtOAc (contains 10% MeOH)/Heptane to give(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-vinyl-5H-imidazo[2′,1′:3,4] pyrazino[1,2-b]pyridazin-10(6H)-one, (52 mg, 0.100 mmol, 64%yield) as a light brown solid. LCMS: MH+523.3, 0.93 min.

Step 2:(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbaldehyde

To (S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-vinyl-5H-imidazo[2′,1′:3,4] pyrazino [1,2-b]pyridazin-10(6H)-one (52 mg, 0.100 mmol) inTHF (Volume: 2 mL) was added sodium periodate (53.2 mg, 0.249 mmol) andosmium tetroxide (0.117 mL, 0.015 mmol) (4% solution in water). Reactionmixture was stirred at RT for 2H. Added 1 eq more of sodium periodateand stirred further 30 min. LCMS showed complete reaction. The ppt wasfiltered off, washed with methanol and the filtrate was concentrated.The residue was partitioned between EtOAc and saturated NaHCO₃ solution.The organic layer was separated, dried over sodium sulfate, filtered andconcentrated to give crude(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbaldehyde, LCMS: MH+525.3,1.07 min.

Step 3:(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-(hydroxymethyl)-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one

The crude (S)-11-(benzyloxy)-6-(bis (4-fluorophenyl)methyl)-10-oxo-6,10-dihydro-5H-imidazo [2′,1′:3,4]pyrazino[1,2-b]pyridazine-3-carbaldehyde (52 mg, 0.100 mmol) from step 2was taken up in MeOH (Volume: 3 mL). The reaction mixture was cooled inice bath then added sodium borohydride (5.27 mg, 0.139 mmol). Thereaction was stirred at ice bath temperature for 30 min. LC-MS showedcomplete reaction. The solvent was evaporated. The crude reactionmixture was partitioned between EtOAc and saturated NaHCO₃ solution. Theorganic layer was separated, dried over sodium sulfate, filtered andevaporated to give crude(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-(hydroxymethyl)-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one, LCMS: MH+527.3, 0.89min.

Step 4:(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5H-imidazopyrazino[1,2-b]pyridazin-10(6H)-one

To crude(S)-11-(benzyloxy)-6-(bis(4-fluorophenyl)methyl)-3-(hydroxymethyl)-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one from step 3 (52 mg, 0.100mmol) was added trifluoroacetic acid (1 ml, 13 mmol). The solution wasthen heated at 80° C. for 25 min in microwave. The reaction wasconcentrated in vacuo and azeotroped with toluene. The crude waspurified by prep HPLC to obtain (S)-6-(bis (4-fluorophenyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5H-imidazo [2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one as a TFA salt, (5.2 mg, 9.26 μmol,18.7% yield). LCMS (m/z): 437.3 (MH+), 0.76 min, 1H NMR (400 MHz, CD3OD)δ ppm 4.29 (d, J=11.05 Hz, 1H) 4.39 (d, J=13.84 Hz, 1H) 4.52-4.62 (m,2H) 4.63-4.73 (m, 1H) 5.81 (dd, J=11.00, 3.52 Hz, 1H) 6.91 (t, J=8.71Hz, 2H) 7.07-7.26 (m, 4H) 7.46 (dd, J=8.58, 5.26 Hz, 2H) 7.53 (d, J=5.62Hz, 2H).

Example 51:(S)-6-((S)-(4-fluorophenyl)(o-tolyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one

Prepared by the method of Example 50. LCMS (m/z): 433.3 (MH+), 0.76 min,1H NMR (400 MHz, CD3OD) δ ppm 1.97 (s, 3H) 4.38 (d, J=13.74 Hz, 1H) 4.49(s, 1H) 4.50-4.54 (m, 1H) 4.57 (s, 1H) 4.60 (s, 1H) 4.66 (br dd,J=14.18, 4.16 Hz, 1H) 5.89 (br dd, J=10.69, 3.30 Hz, 1H) 6.96 (br d,J=7.58 Hz, 1H) 7.02-7.13 (m, 3H) 7.17 (br t, J=7.78 Hz, 1H) 7.35-7.45(m, 3H) 7.48 (s, 1H) 7.66 (br d, J=7.83 Hz, 1H).

Example 52:(S)-6-benzhydryl-11-hydroxy-3-(1H-pyrazol-4-yl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one

Prepared by the method of Example 9, steps 1 and 3 using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.LCMS (m/z): 436.3 (MH+), 0.58 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.68(s, 1H) 7.21-7.47 (m, 14H) 6.18 (d, J=7.14 Hz, 1H) 5.73 (br dd, J=11.47,2.71 Hz, 1H) 4.58 (dd, J=14.01, 3.74 Hz, 1H) 4.41 (d, J=13.74 Hz, 1H)4.15 (d, J=11.54 Hz, 1H).

Example 53: (S)-6-benzhydryl-11-hydroxy-3-phenyl-5H-imidazo [1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Prepared by the method of Example 9, steps 1 and 3 using4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane. LCMS (m/z): 446.3(MH+), 0.73 min, 1H NMR (400 MHz, CD3OD) δ ppm 7.65 (s, 1H) 7.36-7.44(m, 3H) 7.30-7.36 (m, 3H) 7.26-7.29 (m, 1H) 7.19-7.26 (m, 5H) 7.05-7.15(m, 2H) 6.15 (d, J=7.14 Hz, 1H) 5.69 (br dd, J=11.64, 2.69 Hz, 1H) 4.59(br dd, J=13.94, 3.72 Hz, 1H) 4.40 (br d, J=13.89 Hz, 1H) 4.18 (d,J=11.59 Hz, 1H).

Example 54:(S)-6-benzhydryl-11-hydroxy-3-(hydroxymethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde

To (S)-6-benzhydryl-11-(benzyloxy)-3-vinyl-5H-imidazo [1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one (50 mg, 0.103 mmol) in THF (Volume: 3 mL) wasadded sodium periodate (55.1 mg, 0.257 mmol) and osmium tetroxide (0.121mL, 0.015 mmol) (4% solution in water). Reaction mixture was stirred atRT/2H. Added 1 eq more of sodium periodate and stirred further 30 min.LCMS showed complete reaction. The ppt was filtered off, washed withmethanol and evaporated. The residue was partitioned between EtOAc/Satd.NaHCO₃ solution. The organic layer was separated, dried over sodiumsulfate, filtered and evaporated to give crude(S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde,LCMS: MH+488.3, 0.83 min.

Step 2: (S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

The crude(S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde(50 mg, 0.103 mmol) from step 2 was taken in MeOH (Volume: 3.00 mL). Thereaction mixture was cooled in ice bath then added sodium borohydride(5.45 mg, 0.144 mmol). RM was stirred in ice bath 30 min. LC-MS showedcomplete reaction. The solvent was evaporated. The crude reactionmixture was partitioned between EtOAc/Satd. NaHCO₃ solution. The organiclayer was separated, dried over sodium sulfate, filtered and evaporatedto give crude(S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one, LCMS: MH+490.3, 0.76 min.

Step 3: (S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To crude (S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one from step 3 (25 mg, 0.036 mmol)was added trifluoroacetic acid (1 ml, 12.98 mmol). The solution was thenheated at 80° C. for 25 min in microwave. The reaction was concentratedin vacuo and azeotrope with toluene. The crude was purified by Prep HPLCto obtain (S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one as a TFA salt, (3.2 mg, 5.98μmol, 16.7% yield). LCMS (m/z): 400.3 (MH+), 0.59 min, 1H NMR (400 MHz,CD3OD) δ ppm 3.34 (s, 1H) 4.12 (d, J=11.54 Hz, 1H) 4.23 (d, J=13.89 Hz,1H) 4.49-4.53 (m, 1H) 4.53-4.63 (m, 2H) 5.70 (br d, J=13.45 Hz, 1H) 6.10(d, J=7.19 Hz, 1H) 7.21 (s, 4H) 7.26 (d, J=7.24 Hz, 1H) 7.33-7.39 (m,1H) 7.39-7.48 (m, 4H) 7.56 (s, 1H).

Example 55:(6S)-6-benzhydryl-11-hydroxy-3-(1-hydroxyethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1: (6S)-6-benzhydryl-11-(benzyloxy)-3-(1-hydroxyethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To pure (S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde (Example 54, step 1) (30 mg,0.062 mmol) in THF (Volume: 2 mL) was added at −78° C. dropwisemethylmagnesium bromide (0.110 mL, 0.154 mmol). Reaction mixture wasstirred at this temperature for 30 min then slowly warmed to RT. Stirred1H at RT. The reaction was quenched with Satd. NH4Cl and extracted withethyl acetate twice. The combined organic extract was washed with brine,dried over sodium sulfate, filtered and evaporated to give crude(6S)-6-benzhydryl-11-(benzyloxy)-3-(1-hydroxyethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,LCMS: MH+504.2, 0.86 min.

Step 2:(6S)-6-benzhydryl-11-hydroxy-3-(1-hydroxyethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

For synthesis see Example 54, step 3.

LCMS (m/z): 414.3 (MH+), 0.64 min, 1H NMR (400 MHz, CD3OD) δ ppm 1.47(d, J=6.50 Hz, 3H) 4.10 (d, J=11.54 Hz, 1H) 4.39 (q, J=6.55 Hz, 1H) 4.58(d, J=2.20 Hz, 2H) 5.67 (brd, J=11.44 Hz, 1H) 6.09 (d, J=7.19 Hz, 1H)7.17-7.27 (m, 5H) 7.33-7.38 (m, 1H) 7.40-7.48 (m, 4H) 7.50-7.53 (m, 1H).

Example 56: (S)-6-benzhydryl-11-hydroxy-3-(methoxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1: (S)-6-benzhydryl-11-(benzyloxy)-3-(methoxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To crude (S)-6-benzhydryl-11-(benzyloxy)-3-(hydroxymethyl)-5H-imidazo[1,2-a] pyrido [2,1-c] pyrazin-10(6H)-one (Example 54, step 2) (40 mg,0.074 mmol) in DMF (Volume: 1 mL) was added in ice bath, NaH (5.88 mg,0.147 mmol). The reaction mixture was stirred 5-10 min followed by theaddition of iodomethane (0.074 mL, 0.147 mmol). The RM was warm to RTand stirred for 30 min. LC-MS showed complete reaction. The reactionmixture was partitioned between EtOAc/water. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated to givecrude (S)-6-benzhydryl-11-(benzyloxy)-3-(methoxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one, LCMS: MH+504.2, 0.78 min.

Step 2:(S)-6-benzhydryl-11-hydroxy-3-(methoxymethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

For synthesis see Example 54, step 3. LCMS (m/z): 414.3 (MH+), 0.69 min,1H NMR (400 MHz, CD3OD) δ ppm 3.04-3.12 (m, 3H) 4.05-4.23 (m, 2H) 4.40(d, J=13.11 Hz, 1H) 4.46-4.58 (m, 2H) 5.67 (dd, J=11.52, 2.23 Hz, 1H)6.06 (d, J=7.19 Hz, 1H) 7.13-7.28 (m, 6H) 7.32-7.39 (m, 1H) 7.40-7.49(m, 4H) 7.56 (s, 1H).

Example 57:(S)-6-benzhydryl-3-(difluoromethyl)-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-3-(difluoromethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To pure (S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde (Example 54, step 1) (25 mg,0.046 mmol) in DCM (Volume: 1 mL) was added DAST (0.030 ml, 0.231 mmol)at RT. Reaction mixture was then heated at 60° C./5H in heating block.LC-MS showed complete reaction. The reaction mixture was partitionedbetween DCM/Satd. NaHCO₃ solution. The organic layer was separated,dried over sodium sulfate, filtered and evaporated to give(S)-6-benzhydryl-11-(benzyloxy)-3-(difluoromethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,LCMS: MH+510.2, 0.89 min.

Step 2: (S)-6-benzhydryl-3-(difluoromethyl)-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

For synthesis see Example 54, step 3. LCMS (m/z): 420.3 (MH+), 0.77 min,1H NMR (400 MHz, CD3OD) δ ppm 4.15 (d, J=11.69 Hz, 1H) 4.53 (d, J=13.89Hz, 1H) 4.69 (dd, J=13.91, 3.94 Hz, 1H) 5.72 (dd, J=11.64, 3.42 Hz, 1H)6.19 (d, J=7.19 Hz, 1H) 6.75-7.05 (m, 1H) 7.10-7.26 (m, 5H) 7.28-7.50(m, 6H) 7.71 (t, J=2.35 Hz, 1H).

Example 58:(S)-6-benzhydryl-11-hydroxy-3-(trifluoromethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1: (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-iodo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate

To a solution of (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(150 mg, 0.259 mmol) (Intermediate 4.1) in DCM (Volume: 6 mL) was addedTFA (5.7 μl, 0.075 mmol) and NIS (117 mg, 0.518 mmol). Reaction mixturewas heated at 60° C./5H. LC-MS showed major desired product. Reactionmixture was partitioned between DCM and water. The DCM layer wasseparated, washed with brine, dried over sodium sulfate, filtered andevaporated. The crude was purified by silica gel chromatography using0-100% EtOAc (contains 10% MeOH)/Heptane to give (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-iodo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamateas a light brown foamy solid, (80 mg, 0.114 mmol, 43.8% yield). LCMS:MH+703.3, 1.10 min.

Step 2: (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-(trifluoromethyl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate

To (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-iodo-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate(80 mg, 0.114 mmol) in DMF (Volume: 2 mL) was added(1,10-Phenanthroline)(trifluoromethyl)copper(I), (35.6 mg, 0.114 mmol).Stirred at RT/1H. LCMS showed only 10-15% conversion to product. LC-MSshows no change in % product after 5H. Added again(1,10-Phenanthroline)(trifluoromethyl)copper(I), (35.6 mg, 0.114 mmol)and reaction was left stirred at RT/ON. Still desired product waspresent in minor amount. Reaction mixture was diluted with EtOAc andfiltered to remove solid. The EtOAc layer was washed with brine, driedover sodium sulfate, filtered and evaporated to provide crude mixturecontaining starting material and 10-15% of (S)-tert-butyl(34243-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-(trifluoromethyl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamate.LCMS: MH+646.3, 1.21 min. Proceed for next step.

Example 58:(S)-6-benzhydryl-11-hydroxy-3-(trifluoromethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Prepared from (S)-tert-butyl(3-(2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-5-(trifluoromethyl)-1H-imidazol-1-yl)-1,1-diphenylpropan-2-yl)carbamateby the method of Example 7, steps 3-5. LCMS (m/z): 438.3 (MH+), 0.90min, 1H NMR (400 MHz, CD3OD) δ ppm 3.99-4.20 (m, 1H) 4.38 (br d, J=12.91Hz, 1H) 4.69 (br d, J=12.67 Hz, 1H) 5.68 (br s, 1H) 6.05 (br d, J=18.44Hz, 1H) 7.03-7.72 (m, 12H) 7.81-7.92 (m, 1H).

Example 59:(S)-6-benzhydryl-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbonitrile

Prepared from(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one(see Example 7, step 4) by the method of Example 49, steps 2-3. LCMS(m/z): 395.2 (MH+), 1H NMR (500 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.47-7.41(m, 4H), 7.39-7.33 (m, 2H), 7.22 (s, 5H), 6.19 (d, J=7.1 Hz, 1H), 5.73(dd, J=11.2, 3.8 Hz, 1H), 4.64 (dd, J=13.8, 3.8 Hz, 1H), 4.29 (d, J=13.8Hz, 1H), 4.05 (d, J=11.2 Hz, 1H).

Example 60:(S)-6-benzhydryl-11-hydroxy-3-(pyrrolidin-1-ylmethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-3-(pyrrolidin-1-ylmethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

To pure (S)-6-benzhydryl-11-(benzyloxy)-10-oxo-6,10-dihydro-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carbaldehyde (Example 54, step 1) (25 mg,0.046 mmol) in MeOH (Volume: 1 mL) was added acetic acid (7.93 μl, 0.138mmol) and pyrrolidine (0.022 mL, 0.276 mmol). Stirred 5 min then addedsodium triacetoxyborohydride (97.8 mg, 0.462 mmol). The reaction wasquenched with satd. NH4Cl and product was extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate,filtered and evaporated to give crude(S)-6-benzhydryl-11-(benzyloxy)-3-(pyrrolidin-1-ylmethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one,LCMS: MH+543.3, 0.87 min.

Step 2:(S)-6-benzhydryl-11-hydroxy-3-(pyrrolidin-1-ylmethyl)-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)-one

For synthesis see example 54, step 3. LCMS (m/z): 453.3 (MH+), 0.57 min,1H NMR (400 MHz, CD3OD) δ ppm 1.92-2.02 (m, 3H) 2.03 (s, 1H) 4.11 (d,J=11.59 Hz, 1H) 4.25 (br d, J=14.92 Hz, 1H) 4.43 (br d, J=14.87 Hz, 1H)4.50-4.65 (m, 2H) 5.76 (br dd, J=11.59, 2.74 Hz, 1H) 6.05 (d, J=7.24 Hz,1H) 7.08-7.16 (m, 2H) 7.17-7.22 (m, 3H) 7.33-7.53 (m, 6H) 7.65 (s, 1H).

The compounds in this table were prepared by a method similar to Example60.

Example Mass No. Structure M + H 1H NMR 61

413.3 (400 MHz, CD3OD) δ ppm 2.60 (s, 3 H) 2.68 (s, 1 H) 3.87 (d, J =14.87 Hz, 1 H) 3.98 (d, J = 11.49 Hz, 1 H) 4.24 (d, J = 14.92 Hz, 1 H)4.34-4.41 (m, 1 H) 4.51 (dd, J = 13.99, 3.77 Hz, 1 H) 5.69 (br dd, J =11.59, 3.03 Hz, 1 H) 6.01-6.02 (m, 1 H) 6.05 (d, J = 7.29 Hz, 1 H)7.08-7.27 (m, 7H) 7.33- 7.51 (m, 6 H) 7.60 (s, 1 H) 62

485.3 (400 MHz, CD3OD) δ ppm 2.42-2.64 (m, 4 H) 2.67-3.01 (m, 4 H) 3.63(br d, J = 14.18 Hz, 1 H) 3.92 (br d, J = 14.87 Hz, 1 H) 4.23 (d, J =11.64 Hz, 1 H) 4.55-4.65 (m, 1 H) 4.66-4.77 (m, 1 H) 5.76 (dd, J =11.64, 3.57 Hz, 1 H) 6.08 (d, J = 7.19 Hz, 1 H) 7.07- 7.15 (m, 2 H)7.16-7.24 (m, 4 H) 7.34- 7.40 (m, 1 H) 7.41-7.50 (m, 4 H) 7.62 (s, 1 H)63

481.3 (400 MHz, CD3OD) δ ppm 1.11-1.47 (m, 5 H) 1.72 (br d, J = 12.62Hz, 1 H) 1.82-1.95 (m, 2 H) 2.06 (br s, 2 H) 3.03-3.20 (m, 1 H) 3.76 (d,J = 14.87 Hz, 1 H) 3.94 (d, J = 11.40 Hz, 1 H) 4.31 (dd, J = 14.45, 7.16Hz, 2 H) 4.41- 4.53 (m, 1 H) 5.67 (br dd, J = 11.35, 2.64 Hz, 1 H) 6.04(d, J = 7.19 Hz, 1 H) 7.10-7.30 (m, 6 H) 7.31-7.50 (m, 5 H) 7.58 (s, 1H) 64

427.3 (400 MHz, CD3OD) δ ppm 2.59-2.78 (m, 6 H) 3.98-4.20 (m, 2 H) 4.40(d, J = 14.82 Hz, 1 H) 4.47-4.64 (m, 2 H) 5.77 (br d, J = 11.49 Hz, 1 H)6.00- 6.15 (m, 1 H) 7.07-7.16 (m, 2 H) 7.16-7.26 (m, 3 H) 7.34-7.51 (m,5 H) 7.67 (s, 1 H) 65

483.3 (400 MHz, CD3OD) δ ppm 1.62 (qd, J = 11.64, 4.65 Hz, 2 H)1.89-2.03 (m, 2 H) 3.34-3.49 (m, 3 H) 3.80 (d, J = 14.92 Hz, 1 H) 3.95(d, J = 11.44 Hz, 1 H) 4.02 (br d, J = 11.93 Hz, 2 H) 4.28- 4.40 (m, 2H) 4.43-4.52 (m, 1 H) 5.69 (br dd, J = 11.42, 3.11 Hz, 1 H) 6.06 (d, J =7.19 Hz, 1H) 7.09-7.29 (m, 6 H) 7.30-7.54 (m, 5 H) 7.61 (s, 1 H) 66

495.3 (400 MHz, CD3OD) δ ppm 1.06 (d, J = 6.80 Hz, 3 H) 3.01 (dquin, J =14.24, 7.16, 7.16, 7.16, 7.16 Hz, 1 H) 3.63 (d, J = 14.57 Hz, 1 H) 3.81(d, J = 14.57 Hz, 1 H) 4.14 (d, J = 11.59 Hz, 1 H) 4.55 (dd, J = 14.23,3.96 Hz, 1 H) 4.75 (d, J = 14.23 Hz, 1 H) 5.70 (dd, J = 11.49, 3.52 Hz,1 H) 6.08 (d, J = 7.19 Hz, 1 H) 7.13-7.30 (m, 6 H) 7.32- 7.39 (m, 1 H)7.40-7.50 (m, 4 H) 7.54 (s, 1 H) 67

469.3 (400 MHz, CD3OD) δ ppm 2.36-2.79 (m, 4 H) 3.41-3.76 (m, 5 H) 3.85-4.00 (m, 1 H) 4.23 (d, J = 11.64 Hz, 1 H) 4.63 (br dd, J = 14.16, 3.99Hz, 1H) 4.75 (br d, J = 13.60 Hz, 1 H) 5.68- 5.85 (m, 1 H) 6.03-6.19 (m,1 H) 7.06-7.16 (m, 2 H) 7.17-7.28 (m, 4 H) 7.30-7.54 (m, 5 H) 7.65 (d, J= 2.89 Hz, 1H)

Example 68:(S)-6-benzhydryl-11-hydroxy-N,N-dimethyl-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carboxamide

Step 1:(S)-6-benzhydryl-11-(benzyloxy)-N,N-dimethyl-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carboxamide

To an oven-dried 4 mL vial was added(S)-6-benzhydryl-11-(benzyloxy)-3-bromo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one(see Example 7, step 4) (30 mg, 0.056 mmol) and Xantphos-Pd-G2 (5.0 mg,10 mol %). The vial was sealed with a septa-top cap and purged withvacuum/N2 via needle (×3). Toluene (0.55 mL, 0.1 M) was added and thereaction was purged with CO by bubbling through via a needle. Hunig'sbase (15 μl, 0.084 mmol, 1.5 eq) and the dimethylamine (0.17 mmol, 3.0eq) were then added and the reaction was heated to 80 C and stirredunder an atmosphere of CO overnight at which point the product hadprecipitated around the edges of the vial. The reaction was thenconcentrated and used in the next step without further purification.

Step 2:(S)-6-benzhydryl-11-hydroxy-N,N-dimethyl-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carboxamide

For synthesis see example 54, step 3. LCMS (m/z): 441.2 (MH+), 0.76 min.The compounds in the following table were prepared by a method similarto Example 68.

Example Mass No. Structure M + H 1H NMR 69

427.2 (500 MHz, DMSO-d6) δ 8.55 (q, J = 4.5 Hz, 1H), 7.98 (s, 1H),7.45-7.14 (m, 10H), 5.92 (d, J = 7.1 Hz, 1H), 5.80 (dd, J = 11.4, 3.0Hz, 1H), 5.07 (d, J = 14.4 Hz, 1H), 4.54 (dd, J = 14.4, 3.9 Hz, 1H),4.04 (d, J = 11.4 Hz, 2H), 2.68 (d, J = 4.5 Hz, 3H). 70

453.2 71

471.2 Product exists as a ~4:1 rotameric mixture, *indicates minorisomer. (500 MHz, DMSO-d6) δ 8.64 (m, 1H), 8.51* (m, 1H), 8.02 (s, 1H),7.73* (d, J = 6.8 Hz, 1H), 7.44-7.14 (m, 10H), 6.63* (d, J = 7.0 Hz,1H), 6.02* (dd, J = 11.4, 3.0 Hz, 1H), 5.81 (d, J = 7.0 Hz, 1H), 5.74(dd, J = 11.4, 3.0 Hz, 1H), 5.05* (d, J = 14.9 Hz, 1H), 5.02 (d, J =14.7 Hz, 1H), 4.63* (dd, J = 14.9, 3.8 Hz, 0H), 4.51 (dd, J = 14.7, 3.8Hz, 1H), 3.97 (d, J = 11.4 Hz, 1H), 3.86* (d, J = 11.4 Hz, 1H),3.39-3.24 (m, 7H). 72

467.2 Product exists as a ~6:1 rotameric mixture, *indicates minorisomer. (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.82* (s, 1H), 7.75-7.67 (m,10H), 6.65* (d, J = 6.5 Hz, 1H), 6.00* (dd, J = 11.9, 3.3 Hz, 0H), 5.82(d, J = 7.3 Hz, 1H), 5.71 (dd, J = 11.3, 3.3 Hz, 1H), 4.69-4.63 (m, 1H),4.62-4.65* (m, 1H) 4.48 (dd, J = 14.3, 3.5 Hz, 1H), 3.90 (d, J = 11.3Hz, 1H), 3.81-3.71 (m, 4H), 2.05-1.80 (m, 4H)

Example 73:6-benzhydryl-5-cyclopropyl-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Step 1: 3-(benzyloxy)-2-(1H-imidazol-2-yl)-4H-pyran-4-one

To 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (22.3 g, 97 mmol) in MeOH(500 mL) was added glyoxal (40% in water, 19.7 ml, 136 mmol) andammonium acetate (22.40 g, 291 mmol). The reaction was sealed and heatedat 80° C. for 1 hr. The mixture was cooled and concentrated to givecrude 3-(benzyloxy)-2-(1H-imidazol-2-yl)-4H-pyran-4-one, which was usedin the next step without purification. LCMS (m/z): 269.2 (MH+), 0.37min.

Step 2:2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

To 3-(benzyloxy)-2-(1H-imidazol-2-yl)-4H-pyran-4-one (10 g, 37.3 mmol)in DMF (200 mL) at 0° C. was added NaH (2.236 g, 55.9 mmol). Theresulting mix was stirred at 0° C. for 30 min. Dimethylsulfamoylchloride (7.99 mL, 74.6 mmol) was then added dropwise. The cold bath wasremoved and the reaction was stirred at rt for two hours. The mixturewas diluted with EtOAc (400 mL) and washed with water (2×200 mL) andbrine (100 mL). The organic layer was dried (Na2SO4) and concentrated.The residue was purified by silica gel chromatography (10-100% EtOAc inheptane, with 10% MeOH) to give2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(11 g, 29 mmol, 79% yield). LCMS: MH+376.3, 0.82 min.

Step 3:2-(3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

To2-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(10 g, 26.6 mmol) was added NH3 (7.0 M, 10 mL, 70.0 mmol) in MeOH. Thereaction was sealed and heated to 40° C. The reaction was stirred forthree hours, and then concentrated. The residue was purified by silicagel chromatography to give2-(3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(2.1 g, 5.6 mmol, 21% yield). LCMS: MH+375.3, 0.53 min.

Step 4:2-(1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

To2-(3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(2.1 g, 5.61 mmol) in DMF (15 mL) was added Cs2CO3 (2.74 g, 8.41 mmol).The mixture was stirred for 15 minutes andO-(2,4-dinitrophenyl)hydroxylamine (2.234 g, 11.22 mmol) was then added.The mixture was stirred for 2 hours. Most of the solvent was thenremoved via rotovap. The residue was diluted with DCM/MeOH (30/10 mL)and silica gel (20 g). Dry loaded onto silica gel chromatography andeluted with (10-100% EtOAc in heptane, w/10% MeOH) to give2-(1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(1.8 g, 4.6 mmol, 82% yield). LCMS: MH+390.3, 0.55 min.

Step 5: 1-amino-3-(benzyloxy)-2-(1H-imidazol-2-yl)pyridin-4(1H)-one

To2-(1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridin-2-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(1.8 g, 4.62 mmol) in dioxane (30 mL) was added 10% H2SO4 (30 mL). Thereaction was stirred at rt for 5 hours. NaOH (6N) was added to adjust topH 9. The mixture was extracted with EtOAc (5×50 mL). The organic layerwas dried (Na2SO4) and concentrated. The residue was purified by silicagel chromatography (10-100% EtOAc in heptane, w/10% MeOH) to give1-amino-3-(benzyloxy)-2-(1H-imidazol-2-yl)pyridin-4(1H)-one (1.1 g, 3.9mmol, 84% yield). LCMS: MH+283.2, 0.29 min.

Step 6:11-(benzyloxy)-5-cyclopropyl-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To 1-amino-3-(benzyloxy)-2-(1H-imidazol-2-yl)pyridin-4(1H)-one (90 mg,0.319 mmol) in dioxane (1 mL) was added sulfuric acid (1 mL, 0.400mmol). The mixture was stirred for 10 minutes. The solvent wasevaporated on the rotovap (bath temp. 50° C.) and the residue was driedunder high vacuum overnight. The residue was dissolved in MeOH (2 mL)and NaOH (0.4 mL, 1 M) was added to quench sulfuric acid. The mixturewas dried and the residue was washed with MeOH/DCM (1:1, 10 mL). Thesolution was dried to give crude11-(benzyloxy)-5-cyclopropyl-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(100 mg). LCMS: MH+335.3, 0.51 min.

Step 7:5-cyclopropyl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To crude11-(benzyloxy)-5-cyclopropyl-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(100 mg, 0.299 mmol) in TFA (2 mL) was added thioanisole (149 mg, 1.196mmol). The mixture was stirred for one hour. The mixture wasconcentrated and dried under vacuum overnight to give crude5-cyclopropyl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(73 mg). LCMS: MH+245.2, 0.32 min.

Step 8:6-benzhydryl-5-cyclopropyl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one

To crude5-cyclopropyl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(20 mg, 0.082 mmol) in DMF (1 mL) was added sodium hydride (13.1 mg,0.328 mmol) and (bromomethylene)dibenzene (101 mg, 0.409 mmol). Themixture was stirred for 20 minutes at rt. HCl (1N, 0.4 mL) was added toquench the reaction. The resulting mixture was purified by reverse phaseHPLC (MeCN/water with 0.1% TFA) to give, after lyophilization,6-benzhydryl-5-cyclopropyl-11-hydroxy-5H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10(6H)-one(16.8 mg, 26 μmol, 32% yield). LCMS (m/z): 411.3 (MH+), 1H NMR (400 MHz,DMSO-d6) δ 7.91 (d, J=1.6 Hz, 1H), 7.71 (m, 1H), 7.7-7.5 (m, 3H),7.45-7.30 (m, 3H), 7.30-7.10 (m, 5H), 5.78 (d, J=6.1 Hz, 1H), 5.11 (s,1H), 4.95 (d, J=7.0 Hz, 1H), 1.31 (m, 1H), 0.85-0.65 (m, 2H), 0.5-0.3(m, 2H).

Example 74:6-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Prepared by the method of Example 73 using 30% aqueous formaldehyde inDCM/MeOH (2:1) in step 6 and 11-bromo-6,11-dihydrodibenzo[b,e]thiepinein step 8. LCMS (m/z): 415.2 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.61 (m,1H), 7.55-7.38 (m, 3H), 7.35-7.2 (m, 3H), 7.2-7.0 (m, 3H), 6.8-6.7 (m,2H), 5.72 (d, J=6.0 Hz, 1H), 5.7-5.5 (m, 2H), 5.12 (d, J=6.0 Hz, 1H),4.1-3.9 (m, 2H).

Example 75:6-benzhydryl-11-hydroxy-5,5-dimethyl-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Prepared by the method of Example 73 using acetone in step 6. LCMS(m/z): 399.4 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.97 (m, 2H), 7.8-7.6(m, 3H), 7.5-7.4 (m, 2H), 7.30 (d, J=6 Hz, 1H), 7.2-7.0 (m, 3H), 6.8-6.7(m, 2H), 5.92 (d, J=6.0 Hz, 1H), 5.41 (s, 1H), 1.81 (s, 3H), 1.55 (s,3H).

Example 76:5-cyclopropyl-6-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Prepared by the method of Example 73 using11-bromo-6,11-dihydrodibenzo[b,e]thiepine in step 8. LCMS (m/z): 455.2(MH+).

Example 77:6-benzhydryl-11-hydroxy-5-isopropyl-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Prepared by the method of Example 73 using isobutyraldehyde in step 6.LCMS (m/z): 413.2 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H),7.78-7.62 (m, 4H), 7.55-7.3 (m, 4H), 7.3-7.15 (m, 4H), 5.68 (d, J=6.0Hz, 1H), 5.12 (d, J=6.0 Hz, 1H), 4.91 (s, 1H), 1.92 (m, 1H), 1.15 (d,J=7.0 Hz, 3H), 0.85 (d, J=7.0 Hz, 3H).

Example 78:6-benzhydryl-5-ethyl-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one

Prepared by the method of Example 73 using propionaldehyde in step 6.LCMS (m/z): 399.2 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.6-7.55 (m, 4H),7.5-7.35 (m, 4H), 7.3-7.15 (m, 4H), 6.52-6.5 (m, 1H), 5.65 (d, J=6.0 Hz,1H), 5.53-5.1 (m, 1H), 4.96 (s, 1H), 1.72 (m, 2H), 1.05 (d, J=7.0 Hz,3H).

Example 79:6-benzhydryl-11-hydroxy-6H,10H-spiro[imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazine-5,3′-oxetan]-10-one

Prepared by the method of Example 73 using 3-oxetanone and acetic acidin step 6 and reversing the order of steps 7 and 8. LCMS (m/z): 413.3(MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=1.8 Hz, 1H), 7.82 (m, 1H),7.7-7.5 (m, 3H), 7.5-7.38 (m, 3H), 7.34-7.10 (m, 5H), 5.72 (d, J=6.0 Hz,1H), 5.02 (s, 1H), 4.72 (d, J=8.2 Hz, 1H), 4.42 (d, J=8.2 Hz, 1H), 4.36(d, J=8.0 Hz, 1H), 4.05 (d, J=8.2 Hz, 1H).

Example 80:6-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-6H,10H-spiro[imidazo[1,2,4]triazine-5,3′-oxetan]-10-one

Prepared by the method of Example 73 using 3-oxetanone and acetic acidin step 6 and reversing the order of steps 7 and 8 (using11-bromo-6,11-dihydrodibenzo[b,e]thiepine). LCMS (m/z): 457.1 (MH+), 1HNMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.75 (s, 1H), 7.5-7.45 (m, 1H),7.42-7.35 (m, 1H), 7.3-7.05 (m, 4H), 7.0-6.8 (m, 2H), 6.5 (m, 1H), 6.12(d, J=8.0 Hz, 1H), 5.72 (d, J=6.0 Hz, 1H), 5.1 (d, J=8.0 Hz, 1H), 4.91(s, 1H), 4.62 (d, J=8.2 Hz, 1H), 4.32 (d, J=8.2 Hz, 1H), 4.26 (d, J=8.0Hz, 1H), 3.95 (d, J=8.2 Hz, 1H).

Example 81:5-benzhydryl-10-hydroxy-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one

Step 1: 3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl chloride

To a suspension of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (40 g,162 mmol) in DCM (500 mL) was added 1 mL DMF, followed by dropwiseaddition of oxalyl chloride (15.6 mL, 179 mmol). The reaction turnedclear after 30 minutes. After another 30 minutes, the reaction was thenconcentrated and the residue was carried to the next step directly.

Step 2: 1-(tert-butyl) 3-methyl2-(3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl)malonate

To a mixture of tert-butyl methyl malonate (31.1 g, 179 mmol) andmagnesium chloride (17.02 g, 179 mmol) in 350 mL acetonitrile at 0° C.is added triethylamine (100 mL, 715 mmol). The mixture is stirred for 15minutes at 0° C. 3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl chloride (43 g,162 mmol) in acetonitrile (30 mL) is added dropwise. The reactionmixture is allowed to warm to room temperature and stirred for twohours. The reaction mixture is cooled to 0° C. and quenched with 30 mL6N HCl. To the resulting mixture is added 1 L ether and the mixture istransferred to a separatory funnel. The aqueous layer is removed and theorganics are washed with 2×300 mL water followed by washings with brineuntil the ether layer is clear. The organic layer is dried overmagnesium sulphate, filtered, then concentrated to give 1-(tert-butyl)3-methyl 2-(3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl)malonate which isused without further purification.

Step 3: methyl 3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-3-oxopropanoate

To 1-(tert-butyl) 3-methyl2-(3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl)malonate (65 g, 162 mmol) inDCM (200 mL) at RT was added TFA (100 mL). The reaction was stirred forone hour and concentrated. Silica gel chromatography (0-80% EtOAc inheptane) purification provided methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-3-oxopropanoate (42 g, 82%). LCMS(MH+), 303.1, 0.72 min.

Step 4: Methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2-bromo-3-oxopropanoate

To a solution of methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-3-oxopropanoate (5 g, 16.54 mmol)in chloroform (Volume: 60 mL) was added NBS (2.94 g, 16.54 mmol) in 5portions over 2 hour period of time at ambient temperature undernitrogen. The resulting mixture was stirred at 25° C. for 2 h. Reactionwas quenched by adding water. The organic phase was washed with brine,dried over sodium sulfate and filtered. The filtrate was concentrated.The resulting residue was purified by silica gel chromatography(methanol in dichloromethane 0% to 5%) to give methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2-bromo-3-oxopropanoate (3.4 g,8.30 mmol, 50.2% yield). MS m/z 381/383 (M+2).

Step 5: Methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylate

To an ice cold solution of methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2-bromo-3-oxopropanoate (3.4 g,5.35 mmol) in EtOH (Volume: 20 mL) was added methanethioamide (0.687 g,11.24 mmol). The resulting mixture was stirred at 25° C. for 16 h. Thereaction mixture was concentrated and the resulting residue was purifiedon silica gel (ethyl acetate in heptane 0% to 60%) to give methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylate (610 mg, 32%yield). MS m/z 344 (M+1).

Step 6: 4-(3-(Benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylic acid

To an ice cold solution of methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylate (270 mg,0.78 mmol) in mix solvent of THF (Volume: 1.5 mL, Ratio: 1.000), MeOH(Volume: 1.5 mL, Ratio: 1.000) was added 1.0 M lithium hydroxide hydrate(1.02 mL, 1.02 mmol). The resulting mixture was stirred at 55° C. in anoil bath for 1 h. The reaction solution was concentrated and the residuewas diluted with ethyl acetate and water. Then 1.0 M hydrogen chloride(1.02 mL, 1.02 mmol) was added dropwise into the solution. The organicphase was washed with water, brine, dried over sodium sulfate, andfiltered. The filtrate was concentrated. The resulting residue was driedunder high vacuum to give4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylic acid (260 mg,100% yield), MS m/z 330 (M+1).

Step 7: 3-(Benzyloxy)-2-(5-(hydroxymethyl)thiazol-4-yl)-4H-pyran-4-one

To a cold solution of4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazole-5-carboxylic acid (260 mg,0.78 mmol) in THF (Volume: 3.0 mL) at −40° C. was added isobutylchloroformate (0.24 mL, 1.82 mmol) and followed by the addition of4-methylmorpholine (0.20 mL, 1.82 mmol). The resulting mixture wasstirred at −40° C. for 30 min. Then the solution was warmed up to 0° C.and was stirred for another 40 min. The formation of intermediate wasconfirmed by LCMS data. The reaction was continued for 5 h. The reactionsolution was filtered through a filter funnel and the filter cake wasrinsed with 10 ml THF. The combined filtrate was concentrated to half ofthe volume, and the residue was re-cooled to −40° C. At this pointsodium borohydride (29.9 mg, 0.79 mmol) was added followed by theaddition of 0.4 ml water. The resulting mixture was stirred at −35° C.for 20 min, and then was allowed to warm up to ambient temperature andwas stirred for another 1 h.

The reaction mixture was diluted with ethyl acetate and water. And 1 mlHCl (1.0 M) was added dropwise into the solution to bring the pH=5. Theorganic phase was washed with water, saturated sodium bicarbonatesolution, and brine. The organic phase was dried over sodium sulfate,and was filtered. The filtrate was concentrated. The resulting residuewas dried under high vacuum to give3-(benzyloxy)-2-(5-(hydroxymethyl)thiazol-4-yl)-4H-pyran-4-one (54 mg,22% yield), MS m/z 316 (M+1).

Step 8: 3-(Benzyloxy)-2-(5-(bromomethyl)thiazol-4-yl)-4H-pyran-4-one

To a solution of3-(benzyloxy)-2-(5-(hydroxymethyl)thiazol-4-yl)-4H-pyran-4-one (54 mg,0.17 mmol) in DCM (Volume: 1 mL) was added carbon tetrabromide (108 mg,0.32 mmol). The resulting solution was cooled in an ice bath, andfollowed by the addition of triphenylphosphine (90 mg, 0.34 mmol) in 1ml DCM. After addition, the ice bath was removed away and the resultingmixture was stirred at 25° C. for 6 hr. The reaction solution wasconcentrated to remove solvent. The resulting residue was extracted intoether (3×10 ml), the combined ether layer was concentrated to give crudeproduct 3-(benzyloxy)-2-(5-(bromomethyl)thiazol-4-yl)-4H-pyran-4-one (40mg, 65% yield), which was used for next step without purification. MSm/z 378/380 (M+2).

Step 9: Di-tert-butyl1-((4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazol-5-yl)methyl)hydrazine-1,2-dicarboxylate

To an ice cold solution of3-(benzyloxy)-2-(5-(bromomethyl)thiazol-4-yl)-4H-pyran-4-one (40 mg,0.11 mmol) in DMF (Volume: 0.5 mL) was added a mix solution ofdi-tert-butyl hydrazine-1,2-dicarboxylate (34.4 mg, 0.15 mmol) andsodium hydride (5.92 mg, 0.15 mmol) in 1.0 ml DMF. The resulting mixturewas stirred at 0° C. for 10 min, and then was stirred ambienttemperature for 30 min. The reaction solution was diluted with ethylacetate and water, the organic phase was washed with water, brine, driedover sodium sulfate, and was filtered. The filtrate was concentrated togive crude product di-tert-butyl1-((4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazol-5-yl)methyl)hydrazine-1,2-dicarboxylate(35 mg, 63% yield), MS m/z 530 (M+1).

Step 10:3-(Benzyloxy)-2-(5-(hydrazinylmethyl)thiazol-4-yl)-4H-pyran-4-one

To an ice cold solution of di-tert-butyl1-((4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)thiazol-5-yl)methyl)hydrazine-1,2-dicarboxylate(35 mg, 0.066 mmol) in DCM (Volume: 1 mL) was added a cold solution ofTFA (3 ml, 38.9 mmol) in 1.0 ml DCM. The resulting mixture was stirredat 25° C. for 1 h. The reaction solution was concentrated. The residuewas purified by reverse-phase HPLC to give3-(benzyloxy)-2-(5-(hydrazinylmethyl)thiazol-4-yl)-4H-pyran-4-one (10mg, 43.6% yield), MS m/z 330 (M+1).

Step 11:10-(benzyloxy)-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one

To a solution of3-(benzyloxy)-2-(5-(hydrazinylmethyl)thiazol-4-yl)-4H-pyran-4-one (10mg, 0.03 mmol) in MeOH (Volume: 0.5 mL) was added 1 N NaOH (0.09 mL,0.09 mmol). The resulting mixture was stirred at 25° C. for 2 h. Thereaction solution was concentrated to give10-(benzyloxy)-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one(8.0 mg, 85% yield), MS m/z 312 (M+1).

Step 12:5-Benzhydryl-10-hydroxy-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one

To an ice cooled solution of10-(benzyloxy)-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one(8 mg, 0.026 mmol) and diphenylmethanol (9.47 mg, 0.051 mmol) in aceticacid (Volume: 0.5 ml) was added concentrated sulfuric acid (0.014 ml,0.25 mmol). The reaction mixture was heated to 75° C. in an oil bath for15 min. The oil bath temperature was raised to 90° C., and the reactionmixture was heated for 30 min. Cold water (2 ml) was added to reactionmixture, and the resulting mixture was extracted with ethyl acetate (2ml). The organic phase was concentrated. The crude product was purifiedby reverse-phase HPLC (MeCN/water with 0.1% TFA) to give5-benzhydryl-10-hydroxy-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one(1.5 mg, 11% yield) as TFA salt. MS m/z 388.3 (M+1), 0.70 min.

Example 82:5-benzhydryl-10-hydroxy-3-methyl-4,5-dihydroimidazo[4,5-d]pyrido[1,2-b]pyridazin-9(3H)-one

Step 1: methyl 3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2,3-dioxopropanoate

A solution of methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-3-oxopropanoate (6 g, 19.85 mmol)in acetonitrile (50 mL) was added to a solution of TEMPO (3.72 g, 23.82mmol) in acetonitrile (100 mL), followed 5 minutes later by addition ofDDQ (4.96 g, 21.83 mmol). Another portion of DDQ (4.7 g) was added onehour later. The reaction was stirred for 3 hours and concentrated.Silica gel chromatography (0-100% EtOAc in heptane) provided methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2,3-dioxopropanoate (6 g, 96%).LCMS: (MS+H2O+1, 335.2, 0.65 min).

Step 2: methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazole-5-carboxylate

To a suspension of ammonium acetate (9.75 g, 126 mmol) in HOAc (20 mL)was added methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2,3-dioxopropanoate (4 g, 12.65mmol). The mixture was stirred for 10 minutes and formaldehyde (2.53 g,25.3 mmol) was then added. The reaction mix was then heated to 50° C.for three hours. The reaction mixture was then concentrated to removemost of the HOAc. The residue was then diluted with sat. NaHCO₃ (50 mL)and extracted with IPA/DCM (15%). The organic layer was dried (Na₂SO₄)and concentrated. Silica gel chromatography (0-100% EtOAc in heptanewith 10% MeOH) provided methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazole-5-carboxylate (2.1 g,51%). LCMS: (MS+1, 327.2, 0.44 min).

Step 3: methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1-methyl-1H-imidazole-5-carboxylate

To methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1H-imidazole-5-carboxylate (2.1 g,6.44 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (0.386 g,9.65 mmol). The mixture was stirred for 30 minutes and iodomethane(0.601 mL, 9.65 mmol) was then added dropwise. The mixture was stirredfor another hour and then diluted with EtOAc (20 mL) and quenched withHCl (1 M, 2 mL) and water (10 mL). The aqueous layer was extracted withEtOAc (2×10 mL). The combined organic was dried (Na2SO4) andconcentrated. Silica gel chromatography (0-100% EtOAc in heptane with10% MeOH) provided methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1-methyl-1H-imidazole-5-carboxylate(1.45 g, 66%). LCMS: (MS+1, 341.2, 0.71 min).

Example 82:5-benzhydryl-10-hydroxy-3-methyl-4,5-dihydroimidazo[4,5-d]pyrido[1,2-b]pyridazin-9(3H)-one

Prepared from methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-1-methyl-1H-imidazole-5-carboxylateby the method of Example 81, steps 6-12. LCMS (m/z): 385.1 (MH+), 1H NMR(400 MHz, DMSO-d6) δ (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.6-7.1 (s, 8H),6.7-6.4 (m, 3H), 5.65 (d, J=6.0 Hz, 1H), 4.92 (s, 1H), 5.12 (s, 2H), 3.5(s, 3H).

Example 83:5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[4,5-d]pyrido[1,2-b]pyridazin-9-one

Step 1: methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-5-carboxylate

To a solution of methyl3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-2-bromo-3-oxopropanoate (6.46 g,16.95 mmol) in EtOAc (Volume: 24.2 ml) were added formamide (1.013 ml,25.4 mmol) and AgOTf (6.53 g, 25.4 mmol) and heated at 70° C. forovernight. LC/MS showed good conversion but not complete. Another 1.5equiv. each was added and heated for another overnight. LC/MS showed thereaction complete. After the reaction mixture was cooled to rt, EtOAc(20 mL) & saturated NaCl (20 mL) were added and stirred for 2 h, thesalts (AgBr and AgCl) were filtered and the resulting biphasic solutionwas transferred to a separatory funnel and the layers separated. Theaqueous layer was back extracted with EtOAc, and all the organics werewashed with water, sat. NaHCO₃, 1N HCl and water, dried over Na2SO4,filtered and concentrated to give crude methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-5-carboxylate (1.46 g,26%). LCMS: (MS+1, 328.0, 0.55 min).

Example 83:5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[4,5-d]pyrido[1,2-b]pyridazin-9-one

Prepared from methyl4-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-5-carboxylate by the methodof Example 81, steps 6-12. LCMS (m/z): 371.9 (MH+), 1H NMR (400 MHz,DMSO-d6) δ (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.82-7.05 (m, 11H), 5.63(d, J=6.0 Hz, 1H), 5.05 (s, 1H), 4.78 (m, 1H), 4.2 (m, 1H).

Example 84:5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[5,4-d]pyrido[1,2-b]pyridazin-9-one

Step 1: methyl5-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-4-carboxylate

2-isocyanoacetate (9.01 mL, 100 mmol) was added to a solution of3-(benzyloxy)-4-oxo-4H-pyran-2-carbonyl chloride (13.23 g, 50 mmol) (forsynthesis, see example 81 step 1) and TEA (34.8 ml, 250 mmol) in THF(200 mL). The mixture was stirred overnight at RT. The solvent was thenremoved on a rotary evaporator. The residue was taken up in 300 mL ofethyl acetate and washed once with 100 mL of water. The organic phasewas dried over Na2SO4 and the solvent was removed on a rotaryevaporator. The crude was purified by silica gel chromatography(EtOAc/heptane) to give methyl5-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-4-carboxylate (12.3 g,75%). LCMS: (MS+1, 328.1, 0.71 min).

Example 84:5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[5,4-d]pyrido[1,2-b]pyridazin-9-one

Prepared from methyl5-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)oxazole-4-carboxylate by the methodof Example 81, steps 6-12. LCMS (m/z): 372.1 (MH+), 1H NMR (400 MHz,DMSO-d6) δ (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.82-7.05 (m, 11H), 5.51(d, J=6.0 Hz, 1H), 5.18 (s, 1H), 4.2-3.7 (m, 2H).

Example 85:(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-ylacetate

Added diisopropylethylamine (0.014 mL, 0.080 mmol) followed by acetylchloride (3.06 μl, 0.043 mmol) to a solution of Example 22 (15 mg, 0.033mmol) in DCM (Volume: 1 mL) at RT. Stirred at RT for 20 min, by whichtime LCMS showed complete conversion to product mass. Diluted with DCMand washed with dilute aqueous NaHCO₃ solution. The organic layer wasdried over Na2SO4, filtered and concentrated. The residue was taken upin DMSO and purified by reverse-phase prep HPLC (MeCN/water with 0.1%formic acid as eluent) to give, after lyophilization,(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-ylacetate (13 mg, 0.026 mmol, 79% yield) as a white solid. LCMS (m/z):449.3 (MH+), 1H NMR (400 MHz, DMSO-d6) δ (400 MHz, DMSO-d6) δ 7.55-7.47(m, 3H), 7.45 (s, 1H), 7.34 (d, J=1.0 Hz, 1H), 7.19 (q, J=8.8 Hz, 3H),6.98 (t, J=8.7 Hz, 2H), 6.55 (d, J=3.5 Hz, 1H), 5.79 (d, J=11.5 Hz, 1H),4.72 (dd, J=14.0, 4.1 Hz, 1H), 4.21 (d, J=14.0 Hz, 1H), 3.95 (s, 1H),2.33 (s, 3H).

Example 86:(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-ylisobutyrate

Prepared by the method of Example 85 except using isobutyryl chloride.LCMS (m/z): 477.3 (MH+), 1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=8.7,5.5 Hz, 2H), 7.48 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.19 (q, J=8.6Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 6.80 (s, 2H), 5.79 (d, J=11.6 Hz, 1H),4.72 (dd, J=14.0, 4.0 Hz, 1H), 4.20 (d, J=13.9 Hz, 1H), 3.98 (m, 1H),2.90 (q, J=7.1 Hz, 1H), 1.30 (t, J=6.6 Hz, 6H).

Example 87:(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-yl3-methylbutanoate

Prepared by the method of Example 85 except using isovaleryl chloride.LCMS (m/z): 491.3 (MH+), 1H NMR (400 MHz, MeOD) δ ppm 1.01-1.17 (m, 6H)2.24 (dt, J=13.22, 6.77 Hz, 1H) 2.61-2.70 (m, 2H) 3.97 (d, J=11.44 Hz,1H) 4.34 (d, J=14.08 Hz, 1H) 4.60 (s, 1H) 4.71 (dd, J=14.04, 4.01 Hz,1H) 5.55-5.79 (m, 1H) 6.90 (t, J=8.71 Hz, 2H) 7.07-7.20 (m, 4H) 7.35 (d,J=12.57 Hz, 2H) 7.42 (dd, J=8.63, 5.26 Hz, 2H) 7.49 (s, 1H).

Example 88:(S)-((6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-yl)oxy)methylmethyl carbonate

Added potassium carbonate (13.75 mg, 0.099 mmol) and iodomethyl methylcarbonate (14.3 mg, 0.066 mmol) to a solution of Example 22 (15 mg,0.033 mmol) in DMF (Volume: 332 μl) at 0° C. Stirred at 0° C. for 1 hourand then RT for another hour, by which time LCMS showed completeconversion to product mass. The reaction was filtered to remove solidsand purified by reverse-phase prep HPLC (MeCN/water with 0.1% TFA aseluent) to give, after lyophilization,(S)-((6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11-yl)oxy)methylmethyl carbonate (10 mg, 0.016 mmol, 49% yield) as a white solid. LCMS(m/z): 495.2 (MH+), 1H NMR (400 MHz, DMSO-d6) δ (400 MHz, DMSO-d6) δ7.52-7.41 (m, 4H), 7.36 (s, 1H), 7.25-7.13 (m, 4H), 6.99 (t, J=8.8 Hz,2H), 5.86-5.72 (m, 3H), 4.69 (dd, J=14.0, 4.0 Hz, 1H), 4.20 (d, J=14.0Hz, 1H), 3.95-3.84 (m, 1H), 3.67 (s, 3H).

TABLE 1 Compounds of the Examples. Example No. Structure Name  1

6-Benzhydryl-11-hydroxy-5H- imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10(6H)-one  2

6-(bis(3-fluorophenyl)methyl)-11-hydroxy- 5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one  3

6-benzhydryl-11-hydroxy-5,6-dihydro-10H-[1,2,4]triazolo[5′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one  4

(S)-6-Benzhydryl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)- one  5

(S)-6-Benzhydryl-3-chloro-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1- c]pyrazin-10-one  6

6-benzhydryl-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10- one  7

(S)-6-benzhydryl-3-bromo-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)- one  8

(S)-6-benzhydryl-3-cyclopropyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin- 10(6H)-one  9

(S)-6-benzhydryl-3-ethyl-11-hydroxy-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)- one 10

6-(bis(4-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 11

6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 12

6-(bis(4-fluorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 13

(S)-6-benzhydryl-11-hydroxy-3-methyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10(6H)- one 14

(S)-6-benzhydryl-11-hydroxy-2,3-dimethyl-5H-imidazo[1,2-a]pyrido[2,1-c]pyrazin- 10(6H)-one 15

(S)-6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10(6H)-one 16

(R)-6-(bis(3-chlorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10(6H)-one 17

(S)-6-((R)-(4-fluorophenyl)(phenyl)methyl)- 11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 18

(S)-6-((S)-(4-fluorophenyl)(phenyl)methyl)- 11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 19

(S)-6-((R)-(4-fluorophenyl)(5-fluoropyridin-3-yl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 20

(S)-6-((R)-(4-fluorophenyl)(6- (trifluoromethyl)pyridin-3-yl)methyl)-11-hydroxy-5,6-dihydro-10H- imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10-one 21

(S)-6-((S)-(4-fluorophenyl)(3-(trifluoromethyl)phenyl)methyl)-11-hydroxy- 5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 22

(S)-6-(bis(4-fluorophenyl)methyl)-11- hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 23

(S)-6-(bis(3-fluorophenyl)methyl)-11- hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 24

(S)-6-((S)-(3-fluorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 25

(S)-6-((S)-(3,4-difluorophenyl)(4- fluorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 26

(S)-6-((R)-(3-fluorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 27

(S)-6-((S)-(4-fluoro-2-methylphenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 28

(S)-6-((S)-(4-fluorophenyl)(3-(methylthio)phenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 29

(S)-6-((S)-(2-chlorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 30

(S)-6-((S)-(3-bromophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 31

(S)-6-((S)-(3-chlorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 32

(S)-6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)phenyl)methyl)-11-hydroxy- 5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 33

(S)-6-((S)-(4-chlorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 34

(S)-6-((S)-(3,5-difluorophenyl)(4- fluorophenyl)methyl)-11-hydroxy-5H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin- 10(6H)-one 35

(S)-6-((R)-(2-bromo-4-fluorophenyl)(o-tolyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 36

(S)-6-((R)-(2-bromo-4-fluorophenyl)(3-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 37

(S)-6-((R)-(3-bromo-4- fluorophenyl)(phenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 38

(S)-6-((S)-(4-fluorophenyl)(m-tolyl)methyl)- 11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 39

(S)-6-((R)-(2-bromo-4-fluorophenyl)(4-fluorophenyl)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-10-one 40

(S)-6-((S)-(4-fluorophenyl)(o-tolyl)methyl)-11- hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 41

(S)-6-((R)-(4-fluorophenyl)(p-tolyl)methyl)-11- hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 42

(S)-6-((S)-(4-fluorophenyl)(3-(methylsulfonyl)phenyl)methyl)-11-hydroxy- 5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 43

3-((S)-(4-fluorophenyl)((S)-11-hydroxy-10- oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-6- yl)methyl)benzonitrile 44

2-((S)-(4-fluorophenyl)((S)-11-hydroxy-10- oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-6- yl)methyl)benzonitrile 45

4-((R)-(4-fluorophenyl)((S)-11-hydroxy-10- oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-6- yl)methyl)benzonitrile 46

3-((R)-(3-fluorophenyl)((S)-11-hydroxy-10- oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-6- yl)methyl)benzonitrile 47

(S)-6-(bis(4-fluorophenyl)methyl)-3-bromo- 11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 48

(S)-6-(bis(4-fluorophenyl)methyl)-2,3-dibromo-11-hydroxy-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 49

(S)-6-(bis(4-fluorophenyl)methyl)-11- hydroxy-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazine-3- carbonitrile 50

(S)-6-(bis(4-fluorophenyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 51

(S)-6-((S)-(4-fluorophenyl)(o-tolyl)methyl)-11-hydroxy-3-(hydroxymethyl)-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-10- one 52

(S)-6-benzhydryl-11-hydroxy-3-(1H-pyrazol-4-yl)-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one 53

(S)-6-benzhydryl-11-hydroxy-3-phenyl-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1- c]pyrazin-10-one 54

(S)-6-benzhydryl-11-hydroxy-3- (hydroxymethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 55

(6S)-6-benzhydryl-11-hydroxy-3-(1-hydroxyethyl)-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one56

(S)-6-benzhydryl-11-hydroxy-3- (methoxymethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 57

(S)-6-benzhydryl-3-(difluoromethyl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one 58

(S)-6-benzhydryl-11-hydroxy-3- (trifluoromethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 59

(S)-6-benzhydryl-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1- c]pyrazine-3-carbonitrile 60

(S)-6-benzhydryl-11-hydroxy-3-(pyrrolidin-1-ylmethyl)-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one 61

(S)-6-benzhydryl-11-hydroxy-3- ((methylamino)methyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 62

(S)-6-benzhydryl-11-hydroxy-3- (thiomorpholinomethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 63

(S)-6-benzhydryl-3- ((cyclohexylamino)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1- c]pyrazin-10-one 64

(S)-6-benzhydryl-3-((dimethylamino)methyl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one 65

(S)-6-benzhydryl-11-hydroxy-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10- one 66

(S)-6-benzhydryl-11-hydroxy-3-((((R)-1,1,1-trifluoropropan-2-yl)amino)methyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1- c]pyrazin-10-one 67

(S)-6-benzhydryl-11-hydroxy-3- (morpholinomethyl)-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazin-10-one 68

(S)-6-benzhydryl-11-hydroxy-N,N-dimethyl-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carboxamide 69

(S)-6-benzhydryl-11-hydroxy-N-methyl-10-oxo-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazine-3-carboxamide70

(S)-6-benzhydryl-N-cyclopropyl-11-hydroxy-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3-carboxamide 71

(S)-6-benzhydryl-11-hydroxy-N-(2- methoxyethyl)-10-oxo-5,6-dihydro-10H-imidazo[1,2-a]pyrido[2,1-c]pyrazine-3- carboxamide 72

(S)-6-benzhydryl-11-hydroxy-3-(pyrrolidine-1-carbonyl)-5,6-dihydro-10H-imidazo[1,2- a]pyrido[2,1-c]pyrazin-10-one73

6-benzhydryl-5-cyclopropyl-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1- f][1,2,4]triazin-10-one 74

6-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one 75

6-benzhydryl-11-hydroxy-5,5-dimethyl-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1- f][1,2,4]triazin-10-one 76

5-cyclopropyl-6-(6,11- dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin-10-one 77

6-benzhydryl-11-hydroxy-5-isopropyl-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1- f][1,2,4]triazin-10-one 78

6-benzhydryl-5-ethyl-11-hydroxy-5,6-dihydro-10H-imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazin- 10-one 79

6-benzhydryl-11-hydroxy-6H,10H- spiro[imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazine-5,3′-oxetan]-10-one 80

6-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-11-hydroxy-6H,10H-spiro[imidazo[1,2-d]pyrido[2,1-f][1,2,4]triazine-5,3′-oxetan]-10- one 81

5-benzhydryl-10-hydroxy-4,5-dihydro-9H-pyrido[1,2-b]thiazolo[4,5-d]pyridazin-9-one 82

5-benzhydryl-10-hydroxy-3-methyl-4,5-dihydroimidazo[4,5-d]pyrido[1,2-b]pyridazin- 9(3H)-one 83

5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[4,5-d]pyrido[1,2-b]pyridazin-9-one 84

5-benzhydryl-10-hydroxy-4,5-dihydro-9H-oxazolo[5,4-d]pyrido[1,2-b]pyridazin-9-one 85

(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-11-yl acetate 86

(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-11-ylisobutyrate 87

(S)-6-(bis(4-fluorophenyl)methyl)-10-oxo-5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2- b]pyridazin-11-yl3-methylbutanoate 88

(S)-((6-(bis(4-fluorophenyl)methyl)-10-oxo- 5,6-dihydro-10H-imidazo[2′,1′:3,4]pyrazino[1,2-b]pyridazin-11- yl)oxy)methyl methylcarbonateBiological Assays and Data

The activity of a compound according to the present invention can beassessed by the following in vitro and in vivo methods. Using the testassay described herein, compounds of the invention exhibit inhibitoryefficacy in accordance with Table 2.

Endonuclease Inhibition Assay (PA FP Assay)

Compounds were dissolved and serially diluted in 100% DMSO then 0.5 μlwas transferred to 384-well plates. 50 nM truncated InfluenzaA/victoria/75 PA(1-209) was prepared in assay buffer (20 mM Tris,pH=7.5, 10 mM MgCl₂, 0.01% Tween 20, 100 mM NaCl and 1 mM DTT) and 20 ulwas added to each well of assay plate with compounds, centrifuged for 1min at 1000 rpm and incubated for 30 min at room temperature. 20 μl of20 nM fluorescein-labeled probe[5-(4-(3-carboxy-3-oxopropanoyl)-4-(4-chlorobenzyl)piperidine-1-carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid] in assay buffer was then added, centrifuged for 1 min at 1000 rpmand incubated for 60 min at room temperature.

Fluorescence polarization was measured on Perkin Elmer Envision platereader with excitation at 480 nm and emission at 535 nm and reported inmillipolarization units (mP). IC50 values were determined relative towells containing 125 uM of a compound known to bind to the active siteof PA and uninhibited wells containing 1.25% DMSO.

Influenza Virus Minigenome Assays (RNP Assay)

For influenza A virus minigenome reporter assays, 293T cells weretransfected with expression vectors encoding PB2, PB1, PA, NP proteinsand an influenza A Luciferase reporter plasmid. Cells were harvested inDulbecco's modified Eagle's medium (DMEM) minus phenol red, supplementedwith 10% heat inactivated FBS (fetal bovine serum), 1% sodium pyruvateand 1% L-glutamine (Cellgro, Manassas, Va.). The five plasmids wereco-transfected with Fugene 6 transfection reagent (Promega, Madison,Wis.) with a 1:3 ratio DNA (μg):Fugene 6 (μl), in OptiMEM® (Gibco,Carlsbad, Calif.). Transfections were performed at cell densities of1.8×10⁴ cells/well in 384-well format. Compounds were added 2 hourspost-transfection, and plates were incubated at 37° C., 5% CO₂ for 48hours. Following incubation, cells were lysed and luciferase productionquantified by addition of Britelite Plus® (Perkin-Elmer, Waltham,Mass.). For cell toxicity measurement, CellTiter-Glo® (Promega, Madison,Wis.) was added to treated cells following manufacturer's instructions.

Influenza Virus Neuraminidase Assay (NA Assay)

For influenza NA assays, MDCK cells were plated in Phenol Red-free DMEM(Gibco) supplemented with 2 mM L-Glutamine, 1% sodium pyruvate (Cellgro,Manassas, Va.) and 0.1% BSA at cell densities of 1.8×104 cells/well in384-well format. Compounds were added to the cells 2 hourspre-infection. Infections were performed at MOI 0.005 and the plateswere incubated at 37° C., 5% CO2 for 48 hours. Following incubation,neuraminidase activity was evaluated with the NA assay kit(ThermoFisher, Carlsbad, Calif.). For cell toxicity measurement,CellTiter-Glo® (Promega, Madison, Wis.) was added to treated cellsaccording to manufacturer's instructions.

TABLE 2 Biological Activity of Selected Compounds Example PA FP IC₅₀RNP_Alaska EC₅₀ RNP_CAL_EC₅₀ RNP_Hubei EC₅₀ # (μM) (μM) (μM) (μM)  10.05 0.13 0.11 0.11  2 0.07 0.11 0.11 0.09  3 0.4 1.4 1.1 0.79  4 0.010.18 0.16 0.09  5 0.02 0.22 0.10 0.18  6 0.04 0.15 0.19 0.1  7 0.0090.14 0.17 0.16  8 0.04 0.49 0.15 0.53  9 0.85 0.58 0.59 10 0.29 0.320.82 11 0.16 0.08 0.09 12 0.07 0.8 0.06 13 0.57 0.31 0.30 14 0.1 6.7 4.25.5 15 0.04 0.025 0.019 16 0.96 0.82 0.95 17 0.02 0.03 0.01 0.07 18 0.020.13 0.13 0.16 19 0.04 0.23 0.26 0.49 20 0.3 0.69 0.72 0.74 21 0.0710.052 0.11 22 0.027 0.082 0.01 23 0.05 0.023 0.039 0.036 24 0.009 0.0520.036 0.059 25 0.062 0.056 0.1 26 0.027 0.038 0.051 27 0.05 0.05 0.02728 0.072 0.081 0.078 29 0.07 0.072 0.058 31 0.034 0.037 0.064 32 0.280.25 0.72 33 0.02 0.087 0.11 0.27 34 0.033 0.025 0.034 35 0.098 0.050.11 36 0.021 0.027 0.063 38 0.04 0.043 0.049 0.097 39 0.01 0.025 0.0330.053 40 0.02 0.02 0.032 0.035 42 3.6 2.8 3.8 43 0.02 0.14 0.039 0.17 440.55 0.3 0.31 45 0.076 0.042 0.16 46 0.05 0.15 0.064 0.19 48 5.0 4.3 1249 0.87 0.82 0.56 50 0.43 0.1 0.7 51 0.23 0.09 0.16 52 0.008 5.1 8.30.97 53 0.06 0.54 3 0.19 55 2.6 1.7 6.6 56 0.1 0.28 0.092 0.27 57 0.040.22 0.18 0.58 62 1.9 0.64 1.5 65 4.8 3.5 4.9 66 0.72 0.31 0.63 70 6.41.7 12.3 72 3 1.7 5.5 73 0.39 0.17 74 0.13 0.084 0.26 75 0.1 0.48 0.30.4 76 0.43 0.16 0.67 78 0.04 0.25 0.18 0.34 80 0.17 0.01 0.027 81 2.2 783 0.96 0.97 0.73 84 14 11 16 85 0.019 0.022 0.049 86 0.03 0.021 0.04787 0.027 0.021 0.043 88 0.032 0.042 0.089 Inhibitory Activity ofSelected Compounds on multiple flu strains (NA assay) Example PA FP IC₅₀NA_VIR_H1N1 EC₅₀ NA_VIR_H3N2 NA_Hubei EC₅₀ # (μM) (μM) EC₅₀ (μM) (μM) 300.01 0.045 0.19 0.065 47 0.29 0.84 0.56 54 0.1 2.6 4.6 1.6 58 0.2 1.80.82 59 1.4 5.7 1.2 61 2.3 5.7 3.4 63 3.2 6.1 3.9 64 1.7 4.3 2.4 67 4.110 3.8 68 6.3 32 17 69 15 >50 14 71 19 >50 27 79 0.61 1.5 0.39 82 1 41.4

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: G is H or agroup selected from —C(O)R, —C(O)—OR, —C(R^(G))₂—O—C(O)R,—C(R^(G))₂—O—C(O) —OR, —C(O)—NR₂, and —C(R^(G))₂—O—C(O)NR₂, where each Ris independently H or a group selected from C₁-C₄ alkyl, phenyl,pyridyl, C₃-C₇ cycloalkyl, and a 3-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers; and each R that is not H is optionally substituted with one ortwo groups selected from halo, CN, —OH, amino, C₁₋₄ alkyl, phenyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and each R^(G) isindependently selected from H and C₁₋₄ alkyl; X¹ is CR^(X1) or N, whereR^(X1) is H, halo, C₁₋₆ alkyl, C₁₋₄ haloalkyl, CN, COOH, or a 5-6membered heteroaryl ring containing 1-4 heteroatoms selected from N, Oand S as ring members and optionally substituted by 1-2 groups selectedfrom halo, hydroxy, amino, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy;X² is CR^(X2) or N, where R^(X2) is H, halo, C₁₋₆ alkyl or C₁₋₄haloalkyl; X³ is CR^(X3) or N, where R^(X3) is H, C₁₋₄ alkyl or C₁₋₄haloalkyl; provided that X² is CR^(X2) if either or both of X¹ and X³represent N; R¹ is H, halo, hydroxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₄alkoxy; R² and R³ are independently H, C₁₋₄ alkyl or C₃₋₅ cycloalkyl,wherein each C₁₋₄ alkyl and C₃₋₅ cycloalkyl is optionally substitutedwith one or two groups selected from halo, CN, —OH, C₁₋₄ alkoxy, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; or R² and R³ taken together with thecarbon atom to which both are attached can form a 3-5 memberedcycloalkyl ring or a 3-5 membered cyclic ether ring having one oxygen asa ring member; Ring A is a five-membered heteroaryl ring containing atleast one carbon ring atom and up to four heteroatoms selected from N, Oand S as ring members, wherein Z¹ is N, O or S; Z² and Z³ areindependently CR^(z), N, NR^(z), O or S; and Z⁴ and Z⁵ eachindependently represent C or N, provided Z⁴ and Z⁵ are not bothsimultaneously N, where each R^(z) is independently selected from H,halo, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroarylcontaining one or two heteroatoms selected from N, O and S as ringmembers, C₁₋₄ alkoxy, CN, CON(R⁴)₂ and C₁₋₄ haloalkyl, wherein the C₁₋₄alkyl is optionally substituted with one or two groups selected from—OR⁴, —N(R⁴)₂, COOR⁴, CON(R⁴)₂, and a 5-6 membered heterocyclic ringcontaining one or two heteroatoms selected from N, O and S as ringmembers; R⁴ at each occurrence is independently selected from H, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₆ cycloalkyl, phenyl, a 5-6 memberedheterocyclic ring containing one or two heteroatoms selected from N, Oand S as ring members, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl,and 5-6 membered heterocyclic ring containing one or two heteroatomsselected from N, O and S as ring members are each optionally substitutedwith one or two groups independently selected from halo, —OH, C₁₋₂alkyl, and —O(C₁₋₂ alkyl); and two R⁴ groups directly attached to thesame nitrogen atom can optionally be taken together to form a 4-6membered heterocycle optionally containing an additional heteroatomselected from N, O and S as a ring member and optionally substitutedwith one or two groups selected from halo, —OH, C₁₋₂ alkyl, and —O(C₁₋₂alkyl); Ar¹ and Ar² each represent phenyl or a 5-6 membered heteroarylring containing 1-3 heteroatoms selected from N, O and S as ringmembers, and are each independently substituted with up to three groupsselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, C₂₋₄ alkyne, —S(C₁₋₃ alkyl), —SO₂(C₁₋₃ alkyl), and CN; andAr¹ and Ar² are optionally linked together by a bridge of the formula—C(R^(L))₂-L- to form a tricyclic ring system wherein each Ar¹ and Ar²is optionally substituted by up to two groups independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,C₂₋₄ alkyne, —S(C₁₋₃ alkyl), —SO₂(C₁₋₃ alkyl), and CN, where L isselected from S, S═O, SO₂, O, C(R^(L))₂ and CF₂, and each R^(L) isindependently H or C₁₋₂ alkyl.
 2. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein X¹ is CH.
 3. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein X² is CH or N.
 4. The compound according to claim 1 ora pharmaceutically acceptable salt thereof, wherein X³ is CH.
 5. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein R² and R³ are both H.
 6. The compound according toclaim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is H.7. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein Ring A is selected from imidazole, pyrazole,triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole,thiadiazole, and tetrazole.
 8. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein Z⁵ is C.
 9. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein Z⁴ is N.
 10. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein Z³ is CR^(z) or N. 11.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein ring A is selected from imidazole, pyrazole, triazole andtetrazole.
 12. The compound of claim 1, which is of the formula:

wherein Y represents a group selected from

wherein each R^(y) is independently selected from H, halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₂₋₄ alkyne, and CN, or apharmaceutically acceptable salt thereof.
 13. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein G is H.
 14. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein G is selected from —C(O)R, —C(O)—OR, —CH₂—O—C(O)R and—CH₂—O—C(O)—OR; wherein R is C₁-C₄ alkyl, optionally substituted withone or two groups selected from halo, CN, —OH, amino, phenyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.
 15. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers.
 16. A combination comprising a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof and one or more therapeutically activeco-agents.
 17. A method of treating influenza, comprising administeringto a subject in need thereof a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 18. Acompound according to claim 1 or a pharmaceutically acceptable saltthereof, for use as a medicament.
 19. A compound according to claim 1 ora pharmaceutically acceptable salt thereof, for use in the treatment ofinfluenza.
 20. The compound of claim 1, which is selected from:

or a pharmaceutically acceptable salt thereof.